Method and system for ultrasonic neural modulation in a limb

ABSTRACT

Methods and related systems for modulating neural activity by cyclical blocking of conduction in peripheral neural structures with ultrasound are disclosed. In an aspect, neural activity is blocked cyclically with an ultrasonic blocking stimulus source positioned adjacent a skin surface in a vicinity of a nerve. In an aspect, a conduction block is produced in a sensory nerve. Neural modulation may be used, for example, to modulate an immune or inflammatory response or process.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of the earliest availableeffective filing date(s) from the following listed application(s) (the“Priority Applications”), if any, listed below (e.g., claims earliestavailable priority dates for other than provisional patent applicationsor claims benefits under 35 USC §119(e) for provisional patentapplications, for any and all parent, grandparent, great-grandparent,etc. applications of the Priority Application(s)).

Priority Applications:

The present application constitutes a continuation of U.S patentapplication Ser. No. 13/385,923, titled “METHOD AND SYSTEM FORREVERSIBLE CHEMICAL MODULATION OF NEURAL ACTIVITY”, naming Ralph G.Dacey, Jr., Gregory J. Della Rocca, Colin P. Derdeyn, Joshua L. Dowling,Eleanor V. Goodall, Roderick A. Hyde, Muriel Y. Ishikawa, Jordin T.Kare, Eric C. Leuthardt, Nathan P. Myhrvold, Michael A. Smith, Lowell L.Wood, Jr., Victoria Y.H. Wood, and Gregory J. Zipfel as inventors, filed13 Mar. 2012, which is a continuation-in-part of U.S. patent applicationSer. No. 12/214,758, entitled “METHOD FOR REVERSIBLE CHEMICAL MODULATIONOF NEURAL ACTIVITY”, naming RALPH G. DACEY JR. , Gregory J. Della Rocca,Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A.Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, LOWELL L. WOOD JR., VICTORIA Y. H. WOOD, andGregory J. Zipfel as inventors, filed 18 Jun., 2008, now U.S. Pat. No.8,180,447 granted 15 May 2012; U.S. patent application Ser. No.11/999,721, titled “METHOD AND SYSTEM FOR CYCLICAL NEURAL MODULATIONBASED ON ACTIVITY STATE”, naming Ralph G. Dacey, Jr., Gregory J. DellaRocca, Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, RoderickA. Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, NathanP. Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood,and Gregory J. Zipfel as inventors, filed 5 Dec. 2007, now U.S. Pat. No.8,180,446 granted 15 May 2012; U.S. patent application Ser. No.12/070,332, titled “METHOD FOR MAGNETIC MODULATION OF NEURALCONDUCTION”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca, ColinP. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A. Hyde,Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 15 Feb., 2008, now U.S. Pat. No.8,165,668 granted 24 Apr. 2012; U.S. patent application Ser. No.12/070,369, titled “SYSTEM FOR MAGNETIC MODULATION OF NEURALCONDUCTION”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca, ColinP. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A. Hyde,Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 15 Feb., 2008, now U.S. Pat. No.8,165,669 granted 24 Apr. 2012; U.S. patent application Ser. No.12/070,361, titled “METHOD FOR ELECTRICAL MODULATION OF NEURALCONDUCTION”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca, ColinP. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A. Hyde,Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 15 Feb., 2008, now U.S. Pat. No.8,195,287 granted 5 Jun. 2012; U.S. patent application Ser. No.12/070,331, titled “SYSTEM FOR ELECTRICAL MODULATION OF NEURALCONDUCTION”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca, ColinP. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A. Hyde,Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 15 Feb., 2008, now U.S. Pat. No.8,170,658 granted 1 May 2012; U.S. patent application Ser. No.12/080,787, titled “METHOD FOR THERMAL MODULATION OF NEURAL ACTIVITY”,naming Ralph G. Dacey, Jr., Gregory J. Della Rocca, Colin P. Derdeyn,Joshua L. Dowling, Eleanor V. Goodall, Roderick A. Hyde, Muriel Y.Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P. Myhrvold, MichaelA. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, and Gregory J. Zipfelas inventors, filed 4 Apr. 2008, now U.S. Pat. No. 8,170,659 granted 1May 2012; U.S. patent application Ser. No. 12/080,789, titled “SYSTEMFOR THERMAL MODULATION OF NEURAL ACTIVITY”, naming Ralph G. Dacey, Jr.,Gregory J. Della Rocca, Colin P. Derdeyn, Joshua L. Dowling, Eleanor V.Goodall, Roderick A. Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C.Leuthardt, Nathan P. Myhrvold, Michael A. Smith, Lowell L. Wood, Jr.,Victoria Y.H. Wood, and Gregory J. Zipfel as inventors, filed 4 Apr.,2008, now U.S. Pat. No. 8,170,660 granted 1 May 2012; U.S. patentapplication Ser. No. 12/214,559, titled “METHOD FOR CHEMICAL MODULATIONOF NEURAL ACTIVITY”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca,Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A.Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 18 Jun. 2008;

U.S. patent application Ser. No. 12/214,533, titled “SYSTEM FOR CHEMICALMODULATION OF NEURAL ACTIVITY”, naming Ralph G. Dacey, Jr., Gregory J.Della Rocca, Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall,Roderick A. Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt,Nathan P. Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H.Wood, and Gregory J. Zipfel as inventors, filed 18 Jun. 2008, now U.S.Pat. No. 8,160,695 granted 17 Apr. 2012; U.S. patent application Ser.No. 12/214,557, titled “SYSTEM FOR TRANSDERMAL CHEMICAL MODULATION OFNEURAL ACTIVITY”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca,Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A.Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 18 Jun. 2008, now U.S. Pat. No.8,233,976 granted 31 Jul. 2012; U.S. patent application Ser. No.12/214,558, titled “IMPLANT SYSTEM FOR CHEMICAL MODULATION OF NEURALACTIVITY”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca, Colin P.Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A. Hyde, MurielY. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P. Myhrvold,Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, and GregoryJ. Zipfel as inventors, filed 18 Jun. 2008; and U.S. patent applicationSer. No. 12/214,545, titled “SYSTEM FOR REVERSIBLE CHEMICAL MODULATIONOF NEURAL ACTIVITY”, naming Ralph G. Dacey, Jr., Gregory J. Della Rocca,Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall, Roderick A.Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt, Nathan P.Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, andGregory J. Zipfel as inventors, filed 18 Jun. 2008.

The United States Patent Office (USPTO) has published a notice to theeffect that the USPTO's computer programs require that patent applicantsreference both a serial number and indicate whether an application is acontinuation or continuation-in-part. Stephen G. Kunin, Benefit ofPrior-Filed Application, USPTO Official Gazette Mar. 18, 2003, availableat http://www.uspto.gov/web/offices/com/sol/og/2003/week11/patbene.htm.The present Applicant Entity (hereinafter “Applicant”) has providedabove a specific reference to the application(s) from which priority isbeing claimed as recited by statute. Applicant understands that thestatute is unambiguous in its specific reference language and does notrequire either a serial number or any characterization, such as“continuation” or “continuation-in-part,” for claiming priority to U.S.patent applications. Notwithstanding the foregoing, Applicantunderstands that the USPTO's computer programs have certain data entryrequirements, and hence Applicant is designating the present applicationas a continuation-in-part of its parent applications as set forth above,but expressly points out that such designations are not to be construedin any way as any type of commentary and/or admission as to whether ornot the present application contains any new matter in addition to thematter of its parent application(s).

All subject matter of the Related Applications and of any and allparent, grandparent, great-grandparent, etc. applications of the RelatedApplications is incorporated herein by reference to the extent suchsubject matter is not inconsistent herewith.

SUMMARY

In one aspect, a method of modulating neural activity may includeproducing a reversible conduction block in a peripheral neural structureof a subject with a chemical blocking agent while the subject is in afirst activity state, reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate, and repeating the steps of producing a reversible conductionblock in a peripheral neural structure of a subject with a chemicalblocking agent while the subject is in a first activity state andreversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state.

In another aspect, a method of modulating neural activity may includeproducing a reversible conduction block in a peripheral neural structureof a subject with a chemical blocking agent while the subject is in afirst activity state, reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate by applying a reversing stimulus configured to counter thechemical blocking agent used to produce the reversible conduction blockin the peripheral neural structure of the subject, and repeating thesteps of producing a reversible conduction block in a peripheral neuralstructure of a subject while the subject is in a first activity stateand reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state.

In another aspect, a method of modulating neural activity may includeproducing a reversible conduction block in a peripheral neural structureof a subject with a chemical blocking agent while the subject is in afirst activity state, reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate, repeating the steps of producing a reversible conduction block ina peripheral neural structure of a subject while the subject is in afirst activity state and reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate, determining that producing the reversible conduction block in theperipheral neural structure of the subject while the subject is in afirst activity state results in a desired effect in the subject, andproducing a non-reversible conduction block in the peripheral neuralstructure of the subject.

In still another aspect, a method of modulating neural activity mayinclude producing a reversible conduction block of a subset of nervefibers in a peripheral neural structure of a subject with a chemicalblocking agent while the subject is in a first activity state, reversingthe reversible conduction block of the subset of nerve fibers in theperipheral neural structure of the subject to permit conduction in thesubset of nerve fibers in the peripheral neural structure when thesubject is in a second activity state, and repeating the steps ofproducing a reversible conduction block in the subset of nerve fibers ina peripheral neural structure of a subject while the subject is in afirst activity state and reversing the reversible conduction block inthe subset of nerve fibers in the peripheral neural structure of thesubject to permit conduction in the subset of nerve fibers in theperipheral neural structure when the subject is in a second activitystate.

In addition to the foregoing, other method aspects are as described inthe claims, drawings, and text forming a part of the present disclosure.

In one aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure, a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure and generate a chemical blocking agentcontrol signal for driving delivery of a chemical blocking agent adaptedto reversibly block conduction in the peripheral neural structure of thesubject during at least a portion of the first activity state, and achemical blocking agent source configured to deliver a chemical blockingagent responsive to the chemical blocking agent control signal.

In another aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure, a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure and generate a chemical blocking agentcontrol signal for driving delivery of a chemical blocking agent adaptedto reversibly block conduction in the peripheral neural structure of thesubject during at least a portion of the first activity state, and achemical blocking agent source configured to be worn on the body of thesubject and to deliver a chemical blocking agent responsive to thechemical blocking agent control signal.

In another aspect, a neural modulation system may include a signal inputstructure configured to receive a signal indicative of an activity stateof at least a portion of a body of a subject innervated by a peripheralneural structure, a signal processing portion configured to distinguisha first activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from a secondactivity state of the at least a portion of the body of the subjectinnervated by the peripheral neural structure from the signal receivedat the signal input structure and generate a chemical blocking agentcontrol signal for driving delivery of a chemical blocking agent adaptedto reversibly block conduction in the peripheral neural structure of thesubject during at least a portion of the first activity state, and achemical blocking agent source configured to be positioned beneath atleast a portion of the body of the subject and to deliver a chemicalblocking agent responsive to the chemical blocking agent control signal.

In yet another aspect, a neural modulation system may include a signalinput structure configured to receive a signal indicative of an activitystate of at least a portion of a body of a subject innervated by aperipheral neural structure, a signal processing portion configured todistinguish a first activity state of the at least a portion of the bodyof the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure and generate a chemical blockingagent control signal for driving delivery of a chemical blocking agentadapted to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate, and a chemical blocking agent source configured to be implantedwithin the body of the subject and to deliver a chemical blocking agentresponsive to the chemical blocking agent control signal.

In still, another aspect, a neural modulation system may include asignal input structure configured to receive a signal indicative of anactivity state of at least a portion of a body of a subject innervatedby a peripheral neural structure; a signal processing portion configuredto distinguish a first activity state of the at least a portion of thebody of the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure, generate a chemical blockingagent control signal for driving delivery of a chemical blocking agentadapted to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate, and generate a reversing stimulus control signal for drivingdelivery of a reversing stimulus to counter the chemical blocking agentused to produce the reversible conduction block in the peripheral neuralstructure of the subject; a chemical blocking agent source configured todeliver a chemical blocking agent responsive to the chemical blockingagent control signal; and a reversing stimulus source configured toproduce a reversing stimulus responsive to the reversing stimuluscontrol signal.

In a further aspect, a neural modulation system may include a signalinput structure configured to receive a signal indicative of an activitystate of at least a portion of a body of a subject innervated by aperipheral neural structure; a signal processing portion configured todistinguish a first activity state of the at least a portion of the bodyof the subject innervated by the peripheral neural structure from asecond activity state of the at least a portion of the body of thesubject innervated by the peripheral neural structure from the signalreceived at the signal input structure, generate a chemical blockingagent control signal for driving delivery of a chemical blocking agentadapted to reversibly block conduction in the peripheral neuralstructure of the subject during at least a portion of the first activitystate, determine that producing the reversible conduction block in theperipheral neural structure of the subject while the subject is in afirst activity state results in a desired effect in the subject, andgenerate a non-reversible blocking source control signal for driving anon-reversible blocking source to perform an action adapted forproducing a non-reversible conduction block in the peripheral neuralstructure of the subject; a chemical blocking agent source configured todeliver a chemical blocking agent responsive to the chemical blockingagent control signal; and a non-reversible blocking source configured toperform an action adapted for producing a non-reversible conductionblock in the peripheral neural structure of the subject responsive tothe non-reversible blocking source control signal.

In addition to the foregoing, other system aspects are described in theclaims, drawings, and text forming a part of the present disclosure.

In one or more various aspects, related systems include but are notlimited to circuitry and/or programming, including instructions carriedon signal bearing media, for effecting the herein-referenced methodaspects.

The foregoing is a summary and thus may contain simplifications,generalizations, inclusions, and/or omissions of detail; consequently,those skilled in the art will appreciate that the summary isillustrative only and is NOT intended to be in any way limiting. Inaddition to the illustrative aspects, embodiments, and featuresdescribed above, further aspects, embodiments, and features will becomeapparent by reference to the drawings and the following detaileddescription.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A is an illustration of conduction in a single nerve fiber;

FIG. 1B is an illustration of conduction block in the single nerve fiberdepicted in FIG. 1A;

FIG. 2A is an illustration of conduction in nerve;

FIG. 2B is a cross-sectional view of the nerve depicted in FIG. 2A;

FIG. 2C is an illustration of the effect of a complete conduction blockin the nerve depicted in FIG. 2A;

FIG. 2D is a cross-sectional view of the nerve depicted in FIG. 2C;

FIG. 2E is an illustration of the effect of a partial conduction blockin the nerve depicted in FIG. 2A;

FIG. 2F is a cross-sectional view of the nerve depicted in FIG. 2E;

FIG. 3 is a schematic diagram of a transdermal system for producingconduction block in a peripheral neural structure;

FIG. 4 is a schematic diagram of an implanted system for producingconduction block in a peripheral neural structure;

FIG. 5 is a flow diagram of method of modulating neural activity;

FIG. 6 is an illustration of delivery patterns for blocking stimuli;

FIG. 7 is a flow diagram of method of modulating neural activity;

FIG. 8 is a flow diagram of method of modulating neural activity;

FIG. 9 is an illustration of an embodiment of a system in which achemical blocking agent source is located in an arm band;

FIG. 10 is an illustration of types of blocking stimuli;

FIG. 11A is an illustration of an embodiment of a system in which achemical blocking agent source is located in chair;

FIG. 11B is a detail view of a portion of the system of FIG. 11A;

FIG. 12A is an illustration of an embodiment of a system in which achemical blocking agent source is located in a bed;

FIG. 12B is a close-up view of a portion of FIG. 12A;

FIG. 13 is an illustration of an embodiment of a system in which achemical blocking agent source is implanted within the body of asubject;

FIG. 14 is a flow diagram of a method of modulating neural activity;

FIG. 15 is a block diagram of an example of a neural modulation system;

FIG. 16 is a flow diagram of a method of modulating neural activity;

FIG. 17 is an illustration of an embodiment of a neural modulationsystem with a reversing stimulus source;

FIG. 18 is a flow diagram of a method of modulating neural activity;

FIG. 19 is a flow diagram of a method of modulating neural activity;

FIG. 20 is an illustration of an embodiment of a neural modulationsystem with a non-reversible blocking source;

FIG. 21 is a flow diagram of a method of modulating neural activity;

FIGS. 22A-22C depict examples of chemical blocking agent sources;

FIG. 23 is a block diagram of an example of a neural modulation system;

FIG. 24 is a block diagram of an example of a neural modulation system;

FIG. 25 is a block diagram of another example of a neural modulationsystem;

FIG. 26 is a block diagram of a further example of a neural modulationsystem;

FIG. 27 is a block diagram of a further example of a neural modulationsystem;

FIG. 28 is a block diagram of another example of a neural modulationsystem; and

FIG. 29 is a block diagram of a signal processing portion of a neuralmodulation system.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here.

Although the following terms are known in the art, they are generallydefined below for the convenience of the reader:

Definitions

Central Nervous System (CNS) —the brain, spinal cord, optic nerves andretina.

Peripheral Nervous System (PNS) —all the nerves in the body that lieoutside of the brain and spinal cord, i.e., the cranial nerves, spinalnerves, nerve plexuses, and their associated spinal and autonomicganglia.

Autonomic Nervous System (ANS) —the portion of the nervous system thatregulates involuntary body functions, including heart and circulation,respiration, digestion, temperature regulation, etc. The Autonomicnervous system includes two divisions, the sympathetic nervous systemand the parasympathetic nervous system.

Sympathetic nervous system—the division of the autonomic nervous system,which, broadly speaking, functions to mobilize the body's energy andresources during times of stress and arousal to prepare for “fight orflight”, e.g., it accelerates heart rate, constricts blood vessels,elevates blood pressure, etc.

Parasympathetic nervous system—the division of the autonomic nervoussystem that regulates body functions during relaxed states.

Neuron—a nerve cell, the basic functional unit of the nervous system. Aneuron typically includes a cell body, and one or more processes calledaxons and dendrites.

Axon—An axon is a long slender process of a nerve cell that conductselectrical impulses away from the cell body.

Action Potential—a brief, regenerative change in membrane potential thatpropagates actively along membrane of neuron or other excitable cells.

Dendrite—A dendrite is a process of a nerve cell that conductselectrical impulses toward the cell body. Often, a neuron may havemultiple, relatively short dendrites.

Nerve Fiber—The term “nerve fiber” may be used in connection withperipheral neurons to describe long slender processes (either axons ordendrites) that may conduct electrical impulses away from or toward thecell body.

Nerve—a cable-like bundle of multiple nerve fibers, capable of carryingsignals between the central nervous system and other organs and tissuesof the body. Cranial nerves may connect directly to parts of the brain.

Fascicle—a bundle of nerve fibers within a nerve. Each fascicle issurrounded by a dense sheath of tissue called perineurium, while a groupof fascicles that make up a nerve are surrounded and held together bylooser connective tissue called epineurium.

Nerve Plexus—a region of crossover and regrouping of nerve fibers frommultiple nerves.

Ganglion—in the peripheral nervous system, a cluster of nerve cellbodies; sensory (afferent) ganglia lie along spinal column on the dorsalroots. Autonomic ganglia (containing the cell bodies of autonomicneurons) may lie parallel to the spinal column or in or near theirtarget organs.

Spinal Root—root portion of spinal nerve, as it branches off of spinalcord and passes through bony canal through vertebra.

Methods and systems for modulating neural activity by producingconduction block in peripheral neural structures in a controlled fashionare disclosed herein. Effects of peripheral nerve block depend at leastin part on the type of nerve or nerve fibers blocked and the targetorgan or tissue innervated by the blocked nerve or nerve fibers. It isbelieved that delivery of blocking stimuli to coincide at least in partwith particular activity states in a subject may allow desired effectsof blocking (e.g., modulation of immune or inflammatory response,decrease in pain, etc.) to be produced while limiting inconvenience,discomfort, and/or other undesired effects (numbness, diminished oraltered sensation, decreased muscle force or control, interference withautonomic functions), or for other reasons. For example, blockingstimuli may be delivered during periods of reduced activity of thesubject (including, but not limited to, physical activity, physiologicalactivity, or other measures of activity, in all or a portion of the bodyof the subject). Effects of peripheral nerve block depend at least inpart on the type of nerve or nerve fibers blocked and the target organor tissue innervated by the blocked nerve or nerve fibers.

By way of background, FIGS. 1A and 1B provide a conceptual illustrationof the blocking of conduction of an action potential along a singlenerve fiber. FIG. 1A depicts conduction of action potentials (referredto collectively as “neural activity”) in a single nerve fiber 10 (anelongated nerve process, or axon or dendrite) when no conduction blockis present. Neural activity may be sensed from nerve fiber 10 with, forexample, an electrode 12 located at a first position 14 on nerve fiber10. Sensed neural activity may be represented by trace 16, whichincludes action potentials 18 a, 18 b, 18 c and 18 d occurring at timest_(a), t_(b), t_(c) and t_(d). The direction of conduction of actionpotentials along nerve fiber 10 is indicated by the arrow. Trace 20,which may be sensed with electrode 22 at a second position 24 located ata distance/from first position 14 on nerve fiber 10, includes actionpotentials 18 a, 18 b, 18 c and 18 d occurring at times t_(a)+t_(cd),t_(b)+t_(cd), t_(c)+t_(cd) and t_(d)+t_(cd), where t_(cd) is theconduction delay time, or the time for the action potentials to conductdown nerve fiber 10 from first position 14 to second position 24.Conduction delay time t_(cd) is equal to l/v, where l is the distancebetween first position 14 and second position 24 and v is the conductionvelocity.

FIG. 1B depicts the effect of a conduction block in nerve fiber 10,indicated by cross-hatching in blocked region 30. When conduction isblocked at region 30, action potentials 28 e, 28 f, 28 g and 28 h,occurring at times t_(e), t_(f), t_(g) and t_(h) in trace 26 may besensed with electrode 12 at first position 14. However, conduction ofthe action potentials in the direction indicated by the arrow is blockedso they cannot travel past region 30 to second position 24. Accordingly,trace 32, which may be sensed with electrode 22 at second position 24,will not contain any action potentials.

FIGS. 2A-2F illustrate the effects of complete and partial conductionblock on a nerve made up of multiple nerve fibers. A nerve 50 is shownin longitudinal section in FIG. 2A, and in cross section (taken atsection line 2B-2B) in FIG. 2B. Nerve 50 contains multiple nerve fibers54. An electrode 56 at first position 58 may record a compound signal 60from nerve 50. Compound signal 60 is made up of the summation of actionpotentials produced by multiple individual nerve fibers (e.g., as may beproduced in response to an electrical stimulus or other stimulus thatactivates multiple nerve fibers at substantially the same time). If thedirection of conduction is as indicated by the arrow, an electrode 62 atsecond position 64 may record compound signal 66. Because actionpotentials on individual nerve fibers may travel at different conductionvelocities, action potentials that sum to form compound signal 60 atfirst position 58 may not arrive at second position 64 at the samedelays relative to each other. Accordingly, compound signal 66 mayrepresent the summation of the same action potentials that made upcompound signal 60, but because they arrive at second position 64 atdifferent relative delays, compound signal 66 may have a different shapethan compound signal 60.

FIG. 2C depicts nerve 50 in longitudinal section, with a completeconduction block in region 70, as indicated by cross-hatching.Conduction block is indicated in region 74 in the cross-section of thesame nerve, taken at section line 2D-2D and shown in FIG. 2D. Compoundsignal 75 sensed at first position 58 is unchanged relative to compoundsignal 60 shown in FIG. 1A, but compound signal 76, sensed at secondposition 64 with electrode 62, includes no activity, because conductionof action potentials was blocked in all fibers at the blocked region asindicated at 70 and 74.

FIG. 2E depicts in longitudinal view nerve 50 with a partial conductionblock, with blocked fibers in area 80, as indicated by cross-hatching.Conduction block is indicated by cross-hatching in area 84 in thecross-section shown in FIG. 2F, taken along section line 2F-2F in FIG.2E. Compound signal 85 sensed at first position 58 is unchanged relativeto compound signal 60 as shown in FIG. 2A, but compound signal 86,sensed at second position 64 with electrode 62, is of lower amplitudebecause conduction of action potentials was blocked in the subset offibers passing through the blocked region as indicated at areas 80 and84. Accordingly, compound signal 86 is formed by the summation of actionpotentials from those fibers lying outside of area 80, i.e. fibers lyingwithin region 88 in cross-section of FIG. 2F. As seen in thecross-section of FIG. 2F, when a partial conduction block is produced ina nerve, a subset of the nerve fibers (lying within area 84) may beblocked, and another subset of the nerve fibers (lying within region 88)may conduct as usual. In the example shown in FIG. 2F, the blockedsubset of nerve fibers falls within a particular spatial distribution.In some cases, a subset of nerve fibers within a nerve may be blockedbased on fiber diameter, fiber type, presence of a biomarker, or otherparameter instead of or in addition to the location of the nerve fiberwith the nerve.

As used herein, the term “conduction” encompasses not only theconduction of action potentials along a nerve fiber, but also (unlessthe context dictates otherwise) the conduction or transmission of neuralactivity across a synapse from a pre-synaptic cell to a post-synapticcell, e.g. from a pre-synaptic neuron to a post-synaptic neuron or froma pre-synaptic neuron to a muscle or other end organ. Synaptictransmission may be chemical or electrical (ionic) in nature. Similarly,producing a conduction block in a peripheral neural structure mayinclude blocking conduction of an action potential along a nerve fiber,and/or blocking synaptic transmission from a pre-synaptic cell to apost-synaptic cell. Chemical blocking agents having various mechanismsor sites of action may be used, and unless specifically stated, systemsand/or methods as claimed herein are not limited to the use of chemicalblocking agents operating by specific mechanisms or at specific sites.

Conduction block in peripheral nerves may be produced by application ofchemical blocking agents, as described elsewhere herein, or by variousother approaches as known to those of skill in the art. For example,commonly owned U.S. patent application Ser. No. 11/999,721, titled“METHOD AND SYSTEM FOR CYCLICAL NEURAL MODULATION BASED ON ACTIVITY”filed 5 Dec. 2007, and listing as inventors Ralph G. Dacey, Jr., GregoryJ. Della Rocca, Colin P. Derdeyn, Joshua L. Dowling, Eleanor V. Goodall,Roderick A. Hyde, Muriel Y. Ishikawa, Jordin T. Kare, Eric C. Leuthardt,Nathan P. Myhrvold, Michael A. Smith, Lowell L. Wood, Jr., Victoria Y.H. Wood, Gregory J. Zipfel, which is incorporated herein by reference inits entirety, describes various approaches for blocking conduction inperipheral neural structures.

Ultrasonic stimuli have been shown to produce reversible conductionblock in patients with in painful polyneuropathy (see Hong, “Reversiblenerve conduction block in patients with polyneuropathy after ultrasoundthermotherapy at therapeutic dosage.”; Arch. Phys. Med. Rehabil.;February 1991; pp. 132-137; Vol. 72(2). (Abstract only), which isincorporated herein by reference in its entirety). Ultrasound may alsobe used in nerve stimulation, either alone or in combination withmagnetic or electrical stimuli. See, for example, Norton (“Canultrasound be used to stimulate nerve tissue?”; BioMedical EngineeringOnLine; Published 4 Mar. 2003; and Tsui et al., (“In Vitro Effects ofUltrasound with Different Energies on the Conduction Properties ofNeural Tissue”; ScienceDirect-Ultrasonics; 2005; pp. 560-565; Vol. 43;Elsevier B.V.; both of which are incorporated fully herein by reference.

In some embodiments, a blocking stimulus source or portion thereof maybe located outside the body of the subject, and the blocking stimulusmay pass through the skin and underlying tissue to reach the neuralstructure that is to be blocked. In other embodiment, a blockingstimulus source may be positioned within the body of the subject (eitherpermanently or temporarily). Suitable positioning of the blockingstimulus source will depend upon the type of blocking stimulus sourcebeing used and the type and location of the neural structure to beblocked.

In some embodiments, a blocking stimulus source may be implanted withinthe body of a subject. For example, electrical current may be deliveredvia a tripolar arrangement of ring electrodes in insulating cuff , asdescribed in van den Honert et al. (“A technique for collision block ofperipheral nerve: single stimulus analysis”; IEEE Transactions onbiomedical engineering, May 1981; pp. 373-378; Vol. BME-28), which isincorporated herein by reference in its entirety. Electrical blockingstimuli may be delivered with other types of implantable electrodes,including ring or spiral electrodes designed to fully or partiallyencircle a nerve, or electrodes designed to be positioned adjacent anerve. Implanted electrodes may be connected to a power source within orexternal to the body of the subject, via a wired or wireless connection(see, e.g. US 2006/0190053, which is incorporated herein by reference inits entirety.)

High frequency alternating current delivered, for example, with one ormore electrodes, may be used to produce blocking of neural structures.See, for example, Kilgore and Bhadra (“Nerve conduction block utilizinghigh-frequency alternating current”; Medical & Biological Engineering &Computing; 2004; pp. 394-406; Vol. 42), Zhang et al. (“Simulationanalysis of conduction block in Myelinated axons induced byhigh-frequency biphasic rectangular pulses”; IEEE Transactions onBiomedical Engineering; July 2006; pp. 1433-1436; Vol. 53, No. 7), Zhanget al. (“Mechanism of nerve conduction block induced by high-frequencybiphasic electrical currents”; IEEE Transactions on BiomedicalEngineering; December 2006; pp. 2445-2454; Vol. 53, No. 12.), and Tai etal. (“Simulation analysis of conduction block in unmyelinated axonsinduced by high-frequency biphasic rectangular electrical currents”;IEEE Transactions on Biomedical Engineering; July 2005; pp. 1323-1332;Vol. 52, No. 7), all of which are incorporated herein by reference intheir entirety.

Surface electrodes placed on the skin of a subject over a neuralstructure may be used to stimulate or block a neural structure, e.g. asdescribed in Bostock et al. (“Threshold tracking techniques in the studyof human peripheral nerve”; Muscle & Nerve; February 1998; pp. 137-158),which is incorporated herein by reference in its entirety.

Other sources for blocking and/or excitatory stimuli include thermalsources, which may be made implanted or placed on the body surface (forneural structures located sufficiently near the body surface). Forexample, cooling devices such as Peltier devices or liquid heat-transferdevices may be used to block neural conduction, as described in U.S.Pat. Nos. 6,746,474; 6,364,899; and 6,248,126; which are incorporatedfully herein by reference. Nerves may be activated by thermalstimulation, which may be produced by a resistive element, by lowintensity pulsed infrared (IR) light, for example, as described in Wellset al. (“Biophysical mechanisms of transient optical stimulation ofperipheral nerve; Biophysical Journal; October 2007; pp. 2567-2580;Volume 93) and Wells et al. (“Pulsed laser versus electrical energy forperipheral nerve stimulation”; Journal of Neuroscience Methods; 2007;Vol. 163; pp. 326-337), which are incorporated fully herein byreference, by appropriately configured Peltier devices, or by otherheating elements as known to those of skill in the art.

Various methods of exciting or blocking nerve fibers selectively withrespect to fiber diameter, location within a nerve or nerve bundle, orwithin a fascicle are described, for example, in Tarler and Mortimer(“Selective and independent activation of four motor fascicles using afour contact nerve-cuff electrode”; 2004; IEEE Trans. Neural Syst.Rehab. Eng.”; Vol. 12; pp. 251-257), Vessela et al. (“Peripheral nervemagnetic stimulation: influence of tissue non-homogeneity” BioMedicalEngineering OnLine; 23 Dec. 2003; located at:http://www.biomedical-engineering-online.com/content/2/1/19), Olree andHorch (“Differential activation and block of peripheral nerve fibers bymagnetic fields”; Muscle & Nerve; 2006; pp. 189-196; Vol. 34, WileyPeriodicals), and U.S. Pat. No. 5,540,730, all of which are fullyincorporated herein by reference.

FIG. 3 is a schematic diagram illustrating a neural modulation system100 for modulating neural activity by blocking conduction in at least aportion of a peripheral neural structure 140. A body portion of asubject is indicated generally at 120, including skin surface 130overlying peripheral neural structure 140 (in this example, a peripheralnerve) and surrounding tissue 150. Neural modulation system 100 includeschemical blocking agent source 160, which is capable of deliveringchemical blocking agent 170 to block conduction in region 180 ofperipheral neural structure 140. The neural modulation system 100includes a signal input structure 192 configured to receive a signal 194indicative of an activity state of at least a portion 120 of a body of asubject innervated by a peripheral neural structure 140, a signalprocessing portion 110 configured to distinguish a first activity stateof the at least a portion 120 of the body of the subject innervated byperipheral neural structure 140 from a second activity state of the atleast a portion 120 of the body of the subject innervated by theperipheral neural structure 140 from signal 194 received at the signalinput structure 192 and generate a chemical blocking agent controlsignal 196 for driving delivery of a chemical blocking agent 170.Chemical blocking agent 170 may reversibly block conduction in theperipheral neural structure 140 of the subject during at least a portionof the first activity state. Chemical blocking agent source 160 may beconfigured to deliver a chemical blocking agent responsive to thechemical blocking agent control signal 196. Sensor 190 may sense atleast one parameter indicative of an activity state in the subject,which may be an overall activity level of the subject, or a level of useor activity of a body portion innervated by peripheral neural structure140. A signal 194 from sensor 190 may be connected to signal inputstructure 192 of signal processing portion 110.

Neural modulation system 100, as depicted in FIG. 3, delivers chemicalblocking agent 170 transdermally under control of signal processingportion 110. In general, a chemical blocking agent may be deliveredthrough or across the skin of a subject using either passive or activetransdermal delivery. Passive transdermal delivery methods utilizepassive diffusion of agents across the skin. In the case that passivetransdermal delivery is used, signal processing portion 110 may controlthe release or delivery of chemical blocking agent 170 from chemicalblocking agent source 160 to skin surface 130 and chemical blockingagent 170 may travel through or across the skin by passive diffusion.Active transdermal delivery methods utilize an energy source (which maybe a component of chemical blocking agent source 160) to increase theflux of chemical blocking agent 170 across the skin either by alteringthe barrier function of the skin (primarily the stratum corneum) or byincreasing the energy of the agent molecules. The rate of delivery ofchemical blocking agent 170 through the skin of the subject may beproportional to the overall level of energy applied under control ofsignal processing portion 110.

Different methods of active transdermal agent delivery may use differentforms of energy to increase the flux of an agent across the skin,including, but not limited to, electrical energy (e.g., iontophoresisand electroporation), ultrasonic energy (phonophoresis, sonophoresis),magnetic energy (magnetophoresis), and thermal energy (see, e.g.,Gordon, R. D. and Peterson, T. A; “Transdermal Delivery: 4 Myths abouttransdermal drug delivery,” Drug Delivery Technology;http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=143,which is incorporated herein by reference in its entirety).

A chemical blocking agent may be delivered through or across the skin ofthe subject, as depicted in FIG. 3, or, alternatively, a chemicalblocking agent may be delivered with an implanted (or partiallyimplanted) system, as depicted in FIG. 4.

FIG. 4 depicts in schematic form a neural modulation system 100including implantable neural modulation device 105 including chemicalblocking agent source 160. Neural modulation system 100 for modulatesneural activity by blocking conduction in at least a portion of aperipheral neural structure 140. A body portion of a subject isindicated generally at 120, including skin surface 130, peripheralneural structure 140 (here, a peripheral nerve), and surrounding tissue150. Implantable neural modulation device 105 includes chemical blockingagent source 160, which is capable of delivering chemical blocking agent175 to block conduction in region 180 of peripheral neural structure140. Implantable neural modulation device 105 includes a signal inputstructure 192 configured to receive a signal 199 indicative of anactivity state of at least a portion 120 of a body of a subjectinnervated by a peripheral neural structure 140, a signal processingportion 110 configured to distinguish a first activity state of the atleast a portion 120 of the body of the subject innervated by peripheralneural structure 140 from a second activity state of the at least aportion 120 of the body of the subject innervated by the peripheralneural structure 140 from signal 199 received at the signal inputstructure 192 and generate a chemical blocking agent control signal 193for driving delivery of a chemical blocking agent 175. Chemical blockingagent 175 may reversibly block conduction in the peripheral neuralstructure 140 of the subject during at least a portion of the firstactivity state; chemical blocking agent source 160 may be configured todeliver a chemical blocking agent responsive to the chemical blockingagent control signal 193. Sensor 195 may sense at least one parameterindicative of an activity state in the subject, which may be an overallactivity level of the subject, or a level of use or activity of a bodyportion innervated by peripheral neural structure 140. A signal 199 fromsensor 195 may be connected to signal input structure 192 of signalprocessing portion 115.

Various types of implanted devices may be used for delivering chemicalblocking agents, as will be described in greater detail elsewhereherein. Whether a transdermal or implanted system is used for deliveringa chemical blocking agent, the general approach for controlling deliveryof the chemical blocking agent is similar and is based on an activitystate in the subject, which as noted above may be an overall activitylevel of the subject, or a level of use or activity of a body portioninnervated by peripheral neural structure 140.

The term “activity state” refers to one of at least two possiblecategories of activity that are characterized by and distinguishablefrom each other by one or more quantifiable parameters. Activity mayrefer to overall activity of the subject or use or activity of a bodyportion innervated by the peripheral neural structure. Activity mayinclude or be reflected by physical activity, physiological activity, orother measures or indicators of activity, as described in greater detailelsewhere herein.

For purposes of methods as disclosed herein, at least two activitystates may be defined, with appropriate values or value ranges of theone or more quantifiable parameters associated therewith. The differentactivity states may differ with regard to the level of activity, or, insome cases, the nature of the activity. In some cases, the overallactivity of the subject may be lower in the first activity state than inthe second activity state. For example, the first activity state may bea “sleep state” and the second activity state may be a “waking state.”Alternatively, the first activity state may be a “resting,” “lying down”or “sitting” activity state while the second activity state may be a“moving about,” “standing” or “walking” activity state.

The activity or use of a specific portion of the subject's body, ratherthan the overall activity of the subject, may be of interest. Forexample, the first and second activity states may be defined such thatthe use of a body portion innervated by the peripheral neural structureby the subject is lower in the first activity state than in the secondactivity state. If the body portion innervated by the peripheral neuralstructure is the subject's arm, a low use state may be obtained when thearm is resting in the subject's lap, on an arm rest or table top, or ina sling, while the subject stands or walks. Low use or activity of thesubject's arm may also be obtained while the overall activity of thesubject is low, e.g. the subject is lying down or sleeping. Conversely,a moderate or high use or activity state of a body portion, e.g., thesubject's arm, may be obtained while the subject's overall activitylevel is either high or low. For example, the subject could use the armfor writing, typing, holding a book, knitting, etc. while sittingquietly with a low overall activity level. A subject may also have ahigh use or activity state of, e.g., an arm, in combination with anoverall high activity level. First and second activity states may bephysical activity states of the subject, which in some cases may beoverall physical activity states of the subject, and in some cases maybe physical activity states of a portion of the body of the subjectinnervated by the peripheral neural structure. Activity states may bydefined by various types of muscle activity, relating not only to grossmotor activities, but to fine motor activities, and appropriatelypositioned sensors may detect muscle activity or other relatedparameters corresponding to particular facial expressions or eyemotions, or corresponding to specific actions, such as eating, drinking,talking, or smoking, e.g. as indicated by specific mouth movements.

FIG. 5 illustrates a method of modulating neural activity that may becarried out, for example, using a system as depicted in FIG. 3 or FIG.4. The method shown in FIG. 5 includes the steps of producing areversible conduction block in a peripheral neural structure of asubject with a chemical blocking agent while the subject is in a firstactivity state (step 200), reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate (step 202), and repeating the steps of producing a reversibleconduction block in a peripheral neural structure of a subject with achemical blocking agent while the subject is in a first activity stateand reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state (step 204).

The method of modulating neural activity as shown generally in FIG. 5includes producing a reversible conduction block in a peripheral neuralstructure of a subject, which may be, for example, a peripheral nerve, aspinal root, an autonomic ganglion, or a nerve plexus. A peripheralnerve may be a sensory and/or motor nerve, an autonomic nerve (includingsympathetic and/or parasympathetic nerve fibers, or a mixture ofsensory, motor, sensory-motor, and/or autonomic nerve fibers). Examplesof specific nerves that may be subject to reversible conduction blockinclude the radial nerve, median nerve, ulnar nerve, femoral nerve,obturator nerve, sciatic nerve, popliteal nerve, tibial nerve, peronealnerve, vagus nerve, and facial nerve. The geniculate ganglion is anexample of a specific ganglion that may blocked reversibly.

In the practice of the method outlined in FIG. 5, the first activitystate and the second activity state may be defined in several differentways, depending upon the intended application of the method. In somecases, as discussed previously, the first and second activity states mayrepresent first and second overall activity states of the subject, andin other cases, the use of a body portion innervated by the peripheralneural structure may be of interest, and the first and second activitystates may represent first and second states of use of the innervatedbody portion.

FIG. 6 illustrates sensed activity, represented by trace 250; activitystate as determined from sensed activity, represented by trace 252; andseveral examples of chemical blocking agent delivery patterns, which maybe responsive to the sensed activity, represented by traces 254, 256 and258. Time is indicated on the x-axis. Methods for delivering blockingstimuli (including but not limited to chemical blocking agents),responsive to and/or relative to sensed activity is described in greaterdetail in commonly owned U.S. patent application Ser. No. 11/999,721,which, as noted elsewhere herein, is incorporated herein by reference inits entirety. Trace 250 is an illustration of a sensed activity of thetype that might be detected from a subject over a period of time. Trace250 does not represent any specific type of signal (it could be, forexample, a physiological signal such as a heart rate or respirationrate, or a physical signal such as motion detection or pressure signal).In this example, the activity in the subject is classified into one oftwo possible activity states, a first activity state and a secondactivity state, and it is assumed that higher values of the signalindicate that the subject is more active and lower values of the signalindicate that the subject is less active. By setting an appropriatethreshold value, as indicated at 260, it may be possible to distinguishbetween the first activity state (during which the value of trace 250 isabove the threshold value 260 and the second activity state (duringwhich the value of trace 250 is below the threshold value 260). Trace252 may be an overall activity state (which might be determined fromheart rate, for example) or an activity or use state of a portion of thebody of the subject (which might be determined from activity of aparticular muscle, for example).

Examples of several representative patterns for application of blockingstimuli are also illustrated in FIG. 6. The horizontal axis representstime, while the vertical axis represents delivery rate (e.g., pumpingrate, flux across skin, etc.) Trace 254 depicts a chemical blockingagent delivery pattern that corresponds directly to the activity state,with chemical blocking agent delivered (at first delivery rate, asindicated in FIG. 6) while the subject is in the first activity stateand the delivery of the chemical blocking agent effectively discontinued(e.g., stopped, reduced, or rendered ineffective, as indicated by thelower, second delivery rate in FIG. 6) while the subject is in thesecond activity state. The second delivery rate may be zero, or non-zerobut insufficient to block conduction in the peripheral neural structure.The chemical blocking agent pattern represented by trace 254 includesmultiple blocking periods 270, 272, 274 and 276, during which a chemicalblocking agent sufficient to produce a reversible conduction block of atleast a portion of the peripheral neural structure of the subject isdelivered at a first rate, separated by release periods 280, 282 and284, during which delivery of the chemical blocking agent is effectivelydiscontinued. Blocking periods 270, 272, 274 and 276 coincide with afirst activity state in the subject and release periods 280, 282, 284and 286 coincide at least in part with a second activity state in thesubject.

Trace 256 depicts a chemical blocking agent delivery pattern in which achemical blocking agent is delivered at the onset of the first activitystate and discontinued after a time t_(a) after the onset of the firstactivity state. Trace 258 depicts a chemical blocking agent pattern inwhich a chemical blocking agent is delivered at a time t_(b) after theonset of the first activity state and removed at a time t_(c) after itwas delivered. In this example, the period during which the chemicalblocking agent is delivered may extend into the second activity state inthe subject.

In some applications, the steps of producing a reversible conductionblock in a peripheral neural structure of a subject while the subject isin a first activity state and reversing the reversible conduction block(e.g., by stopping or significantly reducing delivery of the chemicalblocking agent) in the peripheral neural structure of the subject topermit conduction in the peripheral neural structure when the subject isin a second activity state may be repeated over a period of timesufficient to produce a modulation of an immune response in a regioninnervated by the peripheral neural structure.

In some applications, the steps of producing a reversible conductionblock in a peripheral neural structure of a subject while the subject isin a first activity state and reversing the reversible conduction blockin the peripheral neural structure of the subject to permit conductionin the peripheral neural structure when the subject is in a secondactivity state may be repeated over a period of time sufficient toproduce a modulation of an inflammatory response in a region innervatedby the peripheral neural structure.

A chemical blocking agent may be delivered intermittently responsive toactivity state (for example according to a pattern as depicted in FIG.6) until a desired modulation of an immune or inflammatory response isobtained. Modulation of an inflammatory or immune response may beproduced using a method or system as described herein, and may involveproducing a total or partial block to a sensory nerve innervating alimb, join, or digit, to produce an effect e.g. as described in Kane etal., “Protective effect of sensory denervation in inflammatory arthritis(evidence of regulatory neuroimmune pathways in the arthritic joint),”Annals of Rheumatic Disease 2005; 64:325-327. doi:10.1136/ard.2004.022277, or as described in Razavi et al., “TRPV1+sensory neurons control β cell stress and islet inflammation inautoimmune diabetes,” (showing elimination of activity from sensoryneurons innervating the pancreas may prevent development of diabetes);Cell; Dec. 15, 2006; pp. 1123-1135; Vol. 127, each of which isincorporated herein by reference in its entirety.

The amount of time needed to produce modulation of an immune response orinflammatory response may be determined prior to use of the method,based on experimental or clinical data, or the method may be carried outuntil an appropriate modulation of immune or inflammatory response isobtained as determined by measurement of indicators of immune orinflammatory response, as known to those of skill in the art. Forexample, inflammation may be indicated by one or more of swelling,color, temperature, or pain or tenderness, and these parameters may bedetermined qualitatively or quantitatively, as described in U.S. Pat.No. 7,226,426, which is incorporated herein by reference in itsentirety. Inflammation may also be indicated by the presence ofT-lymphocytes or macrophages, which may be detectedimmunohistochemically, for example as described in Rooney, T.;Bresnihan, B.; Andersson, U.; Gogarty, M.; Kraan, M.; Schumacker, H. R.;Ulfgren, A.-K.; Veale, D. J.; Youssef, P. P.; and Tak, P. P;“Microscopic measurement of inflammation in synovial tissue:inter-observer agreement for manual quantitative, semiquantitative andcomputerized digital image analysis”; Annals of Rheumatic Disease; 2007;Vol. 66, pp. 1656-1660; doi:10.1136/ard.2006.0611430; by eosinophils,cytokines, chemokines, and/or leukotrienes, as described in Howarth, P.H.; Persson, C. G. A.; Meltzer, E. O.; Jacobson, M. R.; Durhan, S. R.;and Silkoff, P. E.; “Objective monitoring of nasal airway inflammationin rhinitis”; J. Allergy Clin. Immunol.; 2005; Vol. 115; pp. S414-S441;and by other biomarkers, such as certain 14-3-3 proteins, as describedin Kilani, R. T.; Maksymowych, W. P.; Aitken, A.; Boire, G.; St. Pierre,Y.; Li, Y.; and Ghahary, A.; “Detection of high levels of 2 specificisoforms of 14-3-3 proteins in synovial fluid from patients with joininflammation”; J. Rheumatology; 2007; Vol. 34, No. 8; pp. 1650-1657;each of which is incorporated herein by reference in its entirety.Inflammation may also be indicated by products of tissue degradation,and/or immune response may be indicated by one or more of antibodies,immune cells, or chemical markers of immune response or inflammation, asdescribed in Poole, A. R.; “Immunochemical markers of jointinflammation, skeletal damage and repair: where are we now?”; Annals ofRheumatic Disease; 1994; Vol. 53; pp. 3-5; doi:10.1136/ard.53.1.3, whichis incorporated herein by reference in its entirety.

The amount of time needed to produce modulation of an immune response orinflammatory response will depend upon a number of factors, includingthe nature and pattern of delivery of the chemical blocking agent, theperipheral neural structure in which conduction block is produced, andthe nature of the immune or inflammatory response of concern and thelevel of modulation that is to be produced.

FIG. 7 illustrates variants of the method shown generally in FIG. 5. Themethod of FIG. 7 includes the steps of producing a reversible conductionblock in a peripheral neural structure of a subject with a chemicalblocking agent while the subject is in a first activity state (step200), reversing the reversible conduction block in the peripheral neuralstructure of the subject to permit conduction in the peripheral neuralstructure when the subject is in a second activity state (step 202),receiving an input indicative of an activity state of the subject,wherein the input is indicative of at least one of a first activitystate and a second activity state of the subject (314) and repeating thesteps of producing a reversible conduction block in a peripheral neuralstructure of a subject with a chemical blocking agent while the subjectis in a first activity state and reversing the reversible conductionblock in the peripheral neural structure of the subject to permitconduction in the peripheral neural structure when the subject is in asecond activity state (step 204). In some embodiments, the method mayinclude receiving an input representing physiological activity of thesubject, as indicated at 318, which may include, for example, receivingan input representing the heart rate (as indicated at 320), respirationof the subject (as indicated at 322), brain activity (as indicated at324), peripheral neural (as indicated at 326), muscle activity (asindicated at 328), or body temperature of the subject (as indicated at330). Methods and devices for sensing these and other physiologicalsignals or parameters are well known to those of skill in the art.

A physiological sensor as used in the method of FIG. 7 may be configuredto generate a signal indicative of activity of the heart of the subject,activity of the brain of the subject, activity of a peripheral neuralsystem of the subject, activity of a muscle of the subject, respirationof the subject, body temperature of the subject, or other physiologicalsignals that may be indicative of an activity state of all or a portionof the body of the subject. The detection of these and otherphysiological signals is known to those of skill in the art. Examples ofsome possible physiological signals that may indicate activity of all ora portion of a body of a subject include electroencephalographic signals(EEG), electromyographic signals (EMG), electrocardiographic signals(ECG), electrocardiogram morphology, heart rate, blood pressure, bloodoxygenation, respiration rate, respiratory volume, skin conductivity, orbody temperature (e.g., core temperature, subcutaneous temperature).Receiving an input indicative of an activity state of the subject mayinclude receiving an input representing a rest or waking state of thesubject; for example, rest or waking state of a subject may bedetermined based on physiological parameters (EEG, heart rate,respiration rate, etc.). Specific activity states such as sleep may beindicated by particular chemical indicators, e.g. concentration ofmelatonin or melanin-concentrating hormone (MCH) and orexin/hypocretinor other measures (see, for example, U.S. Patent Publication2005/0215947, and Burdakov, D., Gerasimenko, O., and Verkhratsky, A.“Physiological changes in glucose differentially modulate excitabilityof hypothalamic melanin-concentrating hormone and orexin neurons insitu.” J. Neurosci. 2005, Vol. 25, No. 9, pp. 2429-2433, both of whichare incorporated herein by reference in their entirety).

In other embodiments, receiving an input indicative of an activity stateof the subject may include receiving an input representative of physicalactivity of the subject (as indicated at 332 in FIG. 7). The method mayinclude receiving an input representative of motion of the subject (asindicated at 334), receiving an input representative of the bodyposition or posture of the subject (as indicated at 336), receiving aninput from a pressure sensor (as indicated at 338), receiving an inputfrom a force sensor (as indicated at 340), receiving an input from anaccelerometer (as indicated at 342), receiving an input from a gyro (asindicated at 344), receiving an input from a switch (as indicated at346), such as, for example a mercury switch, or receiving an input froma piezoelectric device (as indicated at 348). Other activity sensingdevices, as known to those of skill in the art, may be used as well. InFIG. 7 and in other figures herein, boxes surrounded by dashed linesrepresent alternative or optional steps or system components.

A rest or waking state may be determined based on physical activity. Forexample, resting state may be associated with a lying down postureand/or low level of motion or activity, while a waking or active statemay be associated with an upright posture and/or a higher level ofactivity. A physical activity sensor may be configured to generate asignal indicative of motion or acceleration of the at least a portion ofthe body of the subject innervated by the peripheral neural structure.In some embodiments, the physical activity sensor may be configured togenerate a signal indicative of a body position or posture of thesubject. Physical activity sensors may sense various aspects of postureor movement (amplitude, frequency, direction, etc.) and may includevarious types of sensors, singly or in combination. For example, seeU.S. Pat. No. 5,031,618, which is incorporated herein by reference inits entirety.

Examples of physiological and physical sensors are provided in TheBiomedical Engineering Handbook, Second Edition, Volume I, J. D.Bronzino, Ed., Copyright 2000, CRC Press LLC, section V, pp. V-1-51-9,which is incorporated herein by reference.

As such, a transdermal or implantable delivery system for delivery ofchemical blocking agent may incorporate one or more sensors such as, forexample, a temperature sensor, a pulse rate sensor, a blood glucosesensor, a blood pressure sensor or a pH sensor under closed-loopfeedback control in which the chemical and/or physiological state of thesubject is monitored to determine the appropriate time for dosing.Examples of transdermal delivery devices with sensors and closed loopfeedback systems are described in U.S. Pat. Nos. 5,224,928 and5,997,501, which are incorporated herein by reference in their entirety.Examples of implantable delivery devices with sensors and closed loopfeedback systems are described in U.S. Pat. Nos. 6,464,687; 6,802,811;7,072,802; and 7,108,680, which are incorporated herein by reference intheir entirety. The implantable device may sense chemical orphysiological states associated with the activity state of the subjectand administer one or more chemical blocking agents accordingly. Forexample, analysis of nerve activity such as sympathetic and vagal tonebalance may be used to assess whether a subject is awake or asleep asdescribed in U.S. Pat. No. 7,319,899, which is incorporated herein byreference in its entirety. In some instances, an implantable deliverysystem may monitor a physiological parameter of a subject which variesas a function of the subject's activity state as described in U.S. Pat.No. 7,167,743, which is incorporated herein by reference in itsentirety.

FIG. 8 illustrates further variants of the method shown generally inFIG. 5. The method of FIG. 8 includes the steps of producing areversible conduction block in a peripheral neural structure of asubject with a chemical blocking agent while the subject is in a firstactivity state (step 200), reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate (step 202), receiving an input indicative of an activity state ofthe subject, wherein the input is indicative of at least one of a firstactivity state and a second activity state of the subject (314) andrepeating the steps of producing a reversible conduction block in aperipheral neural structure of a subject with a chemical blocking agentwhile the subject is in a first activity state and reversing thereversible conduction block in the peripheral neural structure of thesubject to permit conduction in the peripheral neural structure when thesubject is in a second activity state (step 406). The method furtherincludes receiving an input indicative of a user instruction, asindicated at 408.

Receiving an input indicative of a user instruction may includereceiving a signal from a user input device (as indicated at 410), whichmay include, for example, receiving a signal from a voice or soundactivated input (as indicated at 412), a switch or knob (as indicated at414), a keyboard (as indicated at 416), a mouse (as indicated at 418), atouch screen (as indicated at 420), or any sort of input device allowinga user to enter an instruction or select an option from a list ofpossible options, as known to those of skill in the art. Userinstructions may also be received from user-controlled intermediatedevice; e.g., a user instruction may be transmitted from a remotecontroller, a cell phone or remote computer operated by the user. Theuser may be a medical care provider, for example. Instructions may betransmitted electronically, electromagnetically, optically,acoustically, mechanically, or by other methods known to those of skillin the art, via one or more device or transmission media.

Delivery of a chemical blocking agent by a transdermal delivery systemmay be controlled either by the subject or other individual using on/offand/or high/low settings, for example, as described in U.S. Pat. No.5,224,927, which is incorporated herein by reference in its entirety.For example, the subject may choose to turn on the transdermal deliverydevice during times of rest and turn off the device during times ofactivity. As an example, an iontophoresis transdermal delivery methodhas been described for on-demand, controlled dosing of the opioidanalgesic fentanyl for pain management in response to activation of itselectronic circuitry by the patient (Powers I. “Fentanyl HCliontophoretic transdermal system (ITS): clinical application ofiontophoretic technology in the management of acute postoperative pain.”Br. J. Anaesth. 2007, Vol. 98, No. 1, pp. 4-11, which is incorporatedherein by reference in its entirety). In the present context, deliveryof chemical blocking agent would be responsive to activity level(overall activity level of the subject or activity level of a portion ofthe subject's body), rather than to sensation of pain. In someinstances, it may be of benefit to limit the number of doses allowed bythe subject. For example, the transdermal delivery method mayincorporate a preprogrammed number of doses allowed during a given timeperiod.

Receiving an input indicative of a user instruction may includereceiving an input indicative of an instruction to modify a definitionof a first activity state or receiving an input indicative of aninstruction to modify a definition of a second activity state. Forexample, the definition of a first or second activity state may includea threshold level, e.g. as depicted in FIG. 6, at reference number 260.

As depicted in FIG. 8, receiving an input indicative of an activitystate of the subject may in some embodiments include receiving an inputindicative of a user instruction as an alternative to sensing aparameter indicative of the activity state of the subject (e.g., aphysical or physiological activity).

In other embodiments (not depicted), receiving an input indicative of auser instruction may be performed in addition to sensing a parameterindicative of the activity state of the subject. For example, a userinput may be used to override delivery of blocking stimuli determinedfrom a sensed parameter, or to modify a pattern of delivery of blockingstimuli.

In a method as shown generally in FIGS. 5, 7 and 8, producing areversible conduction block in a peripheral neural structure of asubject may include delivering a chemical blocking agent with a chemicalblocking agent source positioned in proximity to the body of thesubject. For example, the chemical blocking agent source may be locatedin or on a wrap adapted to be positioned around at least a portion ofthe body of the subject; in or on a bandage or patch configured to beadhered or secured to at least a portion of skin, tissue or mucousmembrane of the subject; in or on a bracelet, anklet, or cuff configuredto be worn on a limb of the subject; in or on a collar or necklaceconfigured to be worn on a neck of the subject; or in or on a fittedgarment or item of clothing configured to be worn by the subject.

FIG. 9 illustrates an embodiment of a system in which a chemicalblocking agent source 160 is located in an arm band (or bracelet/cuff)462 configured to be worn on a forearm 456 of a subject. Neuralmodulation system 100 includes a signal input structure 192 configuredto receive a signal 454 indicative of an activity state of at least aportion 456 (in this case, the forearm) of a body of a subject 458innervated by a peripheral neural structure 460. Neural modulationsystem 100 includes signal processing portion 110 configured todistinguish a first activity state of the at least a portion 456 of thebody of the subject 458 innervated by the peripheral neural structure460 from a second activity state of the at least a portion 456 of thebody of the subject 458 innervated by the peripheral neural structure460 from the signal 454 received at the signal input structure 192 andgenerate a chemical blocking agent control signal 464 for drivingdelivery of a chemical blocking agent adapted to reversibly blockconduction in the peripheral neural structure 460 of the subject duringat least a portion of the first activity state. Neural modulation system100 also includes chemical blocking agent source 160 configured to beworn on the body of the subject 458 and to deliver a chemical blockingagent responsive to the chemical blocking agent control signal 464.Signal 454 may be produced by sensor 468 in response to activity ofportion 456 of body of subject 458. Sensor 468 may be, for example, anelectrode for sensing electromyographic (EMG) activity reflective ofmuscle activity.

In the example of FIG. 9, chemical blocking agent source 160 includes aniontophoresis system that includes two electrodes, anode 470 and cathode472, with associated reservoirs 474 and 476 of chemical blocking agentand electrolyte, respectively. The device may be powered by battery 478.

In other embodiments, a chemical blocking agent source may be located inor on a wrap adapted to be positioned around at least a portion of thebody of the subject; in or on a bandage or patch configured to beadhered or secured to at least a portion of skin, tissue or mucousmembrane of the subject; in or on a bracelet, anklet, or cuff configuredto be worn on a limb of the subject (e.g. as shown in FIG. 9); in or ona collar or necklace configured to be worn on a neck of the subject; orin or on a fitted garment or item of clothing configured to be worn bythe subject. In some embodiments, the signal processing portion may beconfigured to be worn on the body of the subject. The signal processingportion may be packaged with the chemical blocking agent source in apackage configured to be worn on the body of the subject, e.g. as shownin FIG. 9. In other embodiments, the signal processing portion may beconfigured to be located at a location remote from the body of thesubject.

Iontophoresis, as employed in the system of FIG. 9, uses low voltageelectrical current to drive ionized agents or drugs across the skin.Electric current flows from an anode to a cathode with the skincompleting the circuit, and drives ionized molecules into the skin froma reservoir associated with a transdermal delivery device. Othertransdermal delivery methods include, for example, electroporation andphonophoresis or sonophoresis.

Electroporation uses short, high voltage, electrical pulses to createtransient aqueous pores in the skin through which an agent or drug maybe transported. Phonophoresis or sonophoresis uses low frequencyultrasonic energy to disrupt the stratum corneum. For example, Saliba etal. describe enhanced systemic levels of topical dexamethasone whenapplied in combination with ultrasound pulsed with an intensity of 1.0W/cm² at a frequency of 3-MHz for 5 minutes (Saliba, S., Mistry, D. J.,Perrin, D. H., Gieck, J., and Weltman, A. “Phonophoresis and theabsorption of dexamethasone in the presence of an occlusive dressing.”J. Athletic Training. 2007 Vol. 43, No. 3, pp. 349-354, which isincorporated herein by reference in its entirety). Thermal energy may beused to facilitate transdermal delivery by making the skin morepermeable and by increasing the energy of drug molecules.

In some instances, transdermal delivery of a chemical blocking agent maybe facilitated using microporation induced by an array of microneedles.When applied to the skin, microneedles painlessly create micropores inthe stratum corneum without causing bleeding and lower the resistance todrug diffusion through the skin. In some cases, microneedles may be usedto abrade or ablate the skin prior to transport of an agent or drug. Forexample, a micro-array of heated hollow posts may be used to thermallyablate human skin in preparation for transdermal drug delivery bydiffusion as described in U.S. Published Patent Application2008/0045879, which is incorporated herein by reference in its entirety.Alternatively, an array of microneedles may be designed to activelyinject drug into the skin as described in Roxhed, N., Samel, B.,Nordquist, L., Griss, P., and Stemme, G. “Painless drug delivery throughmicroneedle-based transdermal patches featuring active infusion.” IEEETransactions on Biomedical Engineering, 2008, Vol. 55, No, 3, pp.1063-1071, which is incorporated herein by reference in its entirety.

Transdermal delivery of a chemical blocking agent facilitated by anenergy source may be combined with a method that perforates or abradesthe skin of a subject. For example, a transdermal delivery method maycombine iontophoresis with the use of one or more microprojections toperforate the skin to enhance penetration and delivery of an agent, asdescribed, for example, in U.S. Pat. No. 6,835,184 and U.S. PublishedPatent Application 2006/0036209, which are incorporated herein byreference in their entirety. In another example, an energy source asused in iontophoresis or electroporation may be combined withelectrically-induced ablation of skin cells as described in U.S. Pat.No. 7,113,821, which is incorporated herein by reference in itsentirety.

Delivery of a chemical blocking agent via transdermal methods may becontrolled in a number of ways. Delivery may be performed completelyautomatically with a preset dosage regime, controlled by the subject orother individual (e.g., a medical caregiver), or controlledautomatically by a feedback controller based on the sensed activitystate of the subject. A preset dosage regime may assume active andinactive states of the subject such as, for example, during the daytimeversus the nighttime and as such deliver drug only during the night whenthe subject is sleeping. A transdermal delivery system may automaticallytime the activation and deactivation of an electrical power supply, forexample, for delivery and cessation of delivery of a drug at a variablecontrolled rate at preset or preprogrammed time intervals as describedin U.S. Pat. No. 5,224,928, which is incorporated herein by reference inits entirety. The pre-set dosage regime may be programmed into thetransdermal delivery method at the time of manufacture, and/orprogrammed or reprogrammed subsequent to manufacture one or more times.In some embodiments, the transdermal delivery method may have aremovable computer interface component that can be externally programmedfor a specific drug delivery regime and reinserted into the device, asdescribed in U.S. Pat. No. 6,539,250, which is incorporated herein byreference in its entirety.

FIG. 10 illustrates a number of patterns of chemical blocking agentdelivery. Trace 500 represents the activity state of a subject as afunction of time, as indicated on axis 562. Trace 510 depicts an exampleof a chemical blocking agent that is delivered substantiallycontinuously during each blocking period, with the blocking periodscorresponding to occurrences of a first activity state, as indicated intrace 500.

In other embodiments, a chemical blocking agent sufficient to produce areversible conduction block of at least a portion of a peripheral neuralstructure of a subject may be delivered intermittently in pulses duringthe blocking period. For example, a chemical blocking agent sufficientto produce a reversible conduction block of at least a portion of aperipheral neural structure of a subject may be delivered intermittentlyin pulses at a fixed repetition rate during the blocking period. Traces520 and 530 in FIG. 10 are two examples of blocking stimuli deliveredintermittently during the blocking period. In trace 530, rate ofdelivery of a chemical blocking agent during each pulse varies over timeduring the blocking period. In trace 540, duration of pulses of chemicalblocking agent delivery and intervals between pulses vary over timeduring the blocking period. In some embodiments, the chemical blockingagent may be delivered according to a programmed pattern during at leasta portion of the blocking period. The programmed pattern may specify achemical blocking agent delivery rate that varies over time during theblocking period, as depicted in trace 550. In addition, a programmedpattern may specify rate of delivery of chemical blocking agent duringpulses delivered intermittently during the blocking period, in which theamplitude of the stimulus pulses varies over time during the blockingperiod, as illustrated in trace 530, or in which one or both of theduration of the stimulus pulses or interval between the stimulus pulsesvaries over time during the blocking period, as illustrated in trace540.

Various chemical blocking agents may be used to block nerve conduction.Examples of nerve blocking agents include local anesthetics (e.g. aminoesters such as benzocaine, chloroprocaine, cocaine, cyclomethycaine,dimethocaine, procaine, proparacaine, propoxycaine, and tetracaine, andamino amides such as articaine, bupivacaine, carticaine,cinchocaine/dibucaine, etidocaine, levobupivacaine,lidocaine/lignocaine, mepivacaine, prilocalne, ropivacaine, andtrimecaine), tricyclic antidepressants (e.g. amitriptyline,butriptyline, amoxapine, clomipramine, desipramine, dosulepinhydrochloride, doxepin, imipramine, iprindole, lofepramine,nortriptyline, opipramol, protryptyline, and trimipramine), neurotoxins(e.g. tetrodotoxin, saxitoxin, Botulinum toxin), or any other agent thatblocks nerve conduction. See “Local anaesthetics and nerve conduction;”The Virtual Anaesthesia Textbook;http://www.virtual-anaesthesia-textbook.com; which is incorporatedherein by reference in its entirety. Further examples of chemicalblocking agents include anticholinergics, including muscarinic receptorantagonists (e.g. belladonna alkaloids such as atropine (hyoscyamine)and scopolamine (hyoscine), and or synthetic and semisyntheticsubstances such as darifenacin, dicyclomine, flavoxate, ipratropium,oxybutynin, pirenzepine, solifenacin, tiotropium, tolterodine,tropicamide, and trospium) and nicotinic receptor antagonists (e.g.,ganglionic blocking agents such as mecamylamine and trimethaphan;nondepolarizing neuromuscular blocking agents such as atracurium,cisatracurium, doxacurium, metocurine, mivacurium, pancuronium,pipecuronium, rocuronium, tubocurarine, or vecuronium; or depolarizingneuromuscular blocking agents such as gallamine and succinylcholine).Chemical blocking agents may also include β-adrenergic receptorantagonists (beta blockers), including non-selective agents (e.g.,alprenolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol,oxprenolol, penbutolol, pindolol, propranolol, sotalol, or timolol),β1-selective agents (e.g., acebutolol, atenolol, betaxolol, bisoprolol,celiprolol, esmolol, metoprolol, or nebivolol), mixed α1/β-adrenergicantagonists (e.g., carvedilol, celiprolol, or labetalol), orβ2-selective agents (e.g. butaxamine). Still other chemical blockingagents include analgesics, such as paracetamol, NSAIDs (non-steroidalanti-inflammatory drugs), COX-2 (cyclooxygenase-2) inhibitors, andopiates and morphinomimetics such as morphine, hydromorphone,oxymorphone, diamorphine, diacetylmorphine, methadone, fentanyl,sulfentanil, alfentanil, remifentanil, meperidine, levorphanol, codeine,oxycodone, dihydrocodeine, hydrocodone, and pethidine. Still otherchemical agents may include benzodiazepines, e.g., alprazolam,bromazepam, chlordiazepoxide, clonazepam, diazepam, estazolam,flunitrazepam, flurazepam, lorazepam, lormetazepam, mexazolam,midazolam, nitrazepam, oxazepam, temazepam, or triazolam. Aside from themain neurotransmitters of the peripheral nervous system, acetylcholineand noradrenaline, other neurotransmitters exist, jointly labelednon-noradrenergic, non-cholinergic (NANC) transmitters, and drugs thatalter their effects may also be used as chemical agents to block neuralactivity. Examples of such transmitters include non-peptides (e.g.,adenosine triphosphate, gamma-amino butyric acid, dopamine, or nitricoxide), and peptides (e.g., neuropeptide Y, vasoactive intestinalpeptide, gonadotropin releasing hormone, substance P and calcitoningene-related peptide). Modulators of potassium channels, neurokinin (NK)receptors, and purinergic receptors may also be of use as chemicalblocking agents.

A chemical blocking agent for delivery by a transdermal and/orimplantable device may be formulated alone or in combination with one ormore pharmaceutically acceptable carriers, diluents, excipients, and/orvehicles such as, for example, buffers, surfactants, preservatives,solubilizing agents, isotonicity agents, and stabilizing agents asappropriate. A “pharmaceutically acceptable” carrier, for example, maybe approved by a regulatory agency of the state and/or Federalgovernment such as, for example, the United States Food and DrugAdministration (US FDA) or listed in the U.S. Pharmacopeia or othergenerally recognized pharmacopeia for use in animals, and moreparticularly in humans. Conventional formulation techniques generallyknown to practitioners are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000), which is incorporated herein by reference in itsentirety.

Acceptable pharmaceutical carriers include, but are not limited to, thefollowing: sugars, such as lactose, glucose and sucrose; starches, suchas corn starch and potato starch; cellulose and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, andhydroxymethylcellulose; polyvinylpyrrolidone; cyclodextrin and amylose;powdered tragacanth; malt; gelatin, agar and pectin; talc; oils, such asmineral oil, polyhydroxyethoxylated castor oil, peanut oil, cottonseedoil, safflower oil, sesame oil, olive oil, corn oil and soybean oil;polysaccharides, such as alginic acid and acacia; fatty acids and fattyacid derivatives, such as stearic acid, magnesium and sodium stearate,fatty acid amines, pentaerythritol fatty acid esters; and fatty acidmonoglycerides and diglycerides; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; buffering agents, suchas magnesium hydroxide, aluminum hydroxide and sodium benzoate/benzoicacid; water; isotonic saline; Ringer's solution; ethyl alcohol;phosphate buffer solutions; other non-toxic compatible substancesemployed in pharmaceutical compositions.

The chemical blocking agent may be formulated in a pharmaceuticallyacceptable liquid carrier. The liquid carrier or vehicle may be asolvent or liquid dispersion medium comprising, for example, water,saline solution, ethanol, a polyol, vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The solubility of a chemicalblocking agent may be enhanced using solubility enhancers such as, forexample, water; diols, such as propylene glycol and glycerol;mono-alcohols, such as ethanol, propanol, and higher alcohols; DMSO(dimethylsulfoxide); dimethylformamide, N,N-dimethylacetamide;2-pyrrolidone, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone,1-dodecylazacycloheptan-2-one and othern-substituted-alkyl-azacycloalkyl-2-ones and othern-substituted-alkyl-azacycloalkyl-2-ones (azones). The proper fluiditymay be maintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. One or more antimicrobial agent may beincluded in the formulation such as, for example, parabens,chlorobutanol, phenol, sorbic acid, and/or thimerosal to preventmicrobial contamination. In some instances, it may be preferable toinclude isotonic agents such as, for example, sugars, buffers, sodiumchloride or combinations thereof.

A chemical blocking agent for use in a transdermal delivery method maybe formulated to enhance transit of the agent through the skin. Forexample, water-insoluble, stratum corneum-lipid modifiers such as forexample 1,3-dioxanes, 1,3-dioxolanes and derivatives thereof, 5-, 6-,7-, or 8-numbered lactams (e.g., butyrolactam, caprolactam), morpholine,cycloalkylene carbonate have been described for use in transdermaliontophoresis (see, e.g., U.S. Pat. No. 5,527,797, which is incorporatedherein by reference in its entirety). Other lipid bilayer disruptersinclude but are not limited to ethanol, polyethylene glycol monolaurate,azacycloalkan-2-ones, linoleic acid, capric acid, lauric acid,neodecanoic acid (in ethanol or propylene glycol, for example).

In some instances, the chemical blocking agent may be formulated in adispersed or dissolved form in a hydrogel or polymer associated witheither an implantable or a transdermal delivery method. Examples ofhydrogels and/or polymers include but are not limited to gelled and/orcross-linked water swellable polyolefins, polycarbonates, polyesters,polyamides, polyethers, polyepoxides and polyurethanes such as, forexample, poly(acrylamide), poly(2-hydroxyethyl acrylate),poly(2-hydroxypropyl acrylate), poly(N-vinyl-2-pyrrolidone),poly(n-methylol acrylamide), poly(diacetone acrylamide),poly(2-hydroxylethyl methacrylate), poly(allyl alcohol). Other suitablepolymers include but are not limited to cellulose ethers, methylcellulose ethers, cellulose and hydroxylated cellulose, methyl celluloseand hydroxylated methyl cellulose, gums such as guar, locust, karaya,xanthan gelatin, and derivatives thereof. For iontopheresis, forexample, the polymer or polymers may include an ionizable group such as,for example, (alkyl, aryl or aralkyl) carboxylic, phosphoric, glycolicor sulfonic acids, (alkyl, aryl or aralkyl) quaternary ammonium saltsand protonated amines and/or other positively charged species asdescribed in U.S. Pat. No. 5,558,633, which is incorporated herein byreference in its entirety.

Information regarding formulation of FDA approved chemical blockingagents may be found in the package insert and labeling documentationassociated with each approved agent. A compendium of package inserts andFDA approved labeling may be found in the Physicians Desk Reference.Alternatively, formulation information for approved chemical blockingagents may be found on the internet at websites such as, for example,www.drugs.com and www.rxlist.com. For example, the liquid form ofdiazepam (Valium) contains active drug, benzyl alcohol as preservative,propylene glycol, ethanol, and is buffered with sodium benzoate andbenzoic acid and the pH adjusted with sodium hydroxide. For thosechemical blocking agents which do not currently have a formulationappropriate for use in an implanted device, an appropriate formulationmay be determined empirically and/or experimentally using standardpractices.

As an alternative to systems as illustrated in FIG. 9, in which achemical blocking agent source is worn on the body of the subject, inother embodiments, a reversible conduction block may be produced in aperipheral neural structure of a subject with a chemical blocking agentsource configured to be positioned beneath at least a portion of thebody of the subject. For example, in various embodiments, the chemicalblocking agent source may be located in or on a chair, bed, pad,cushion, or any other structure on which at least a portion of the bodyof the subject may rest. If only a portion of the subject's body is tobe subjected to the chemical blocking agent, a structure having a sizeand structure suited to the portion of the body may be used. Forexample, if the body portion is the lower leg, the chemical blockingagent source may be included in a footstool, for example. If the bodyportion is the arm, the chemical blocking agent source may be includedin a table top, arm rest, or sling. If the chemical blocking agentsource is included in a pad or cushion of an appropriate size, the pador cushion may be placed on any surface (a chair, stool, table top, thesubject's lap, a bed, the ground, etc.) and the body portion may then bepositioned above the pad or cushion.

For transdermal delivery methods as disclosed herein, close contact ofat least a portion of the delivery device with the skin (sufficient fortransmission of e.g., chemicals or electrical, magnetic, thermal,acoustic or other forms of energy) may be provided by placing theportion of the delivery device against bare skin, or by providingportions of the delivery device (e.g., needles or microneedles) that arecapable of penetrating a layer of clothing or bedding interposed betweenthe delivery device and the skin of the subject.

FIG. 11A depicts an embodiment of a neural modulation system 100 inwhich a chemical blocking agent source 160 is located in chair 604 onwhich the subject 606 may be seated. In the embodiment of FIG. 11A,neural modulation system 100 includes a signal input structure 192configured to receive a signal 610 indicative of an activity state of atleast a portion 612 of a body of a subject 606 (in this example, aportion of the leg of subject 606) innervated by a peripheral neuralstructure 614. Neural modulation system 100 may also include a signalprocessing portion 110 configured to distinguish a first activity stateof the at least a portion 612 of the body of the subject 606 innervatedby the peripheral neural structure 614 from a second activity state ofthe at least a portion 612 of the body of the subject 606 innervated bythe peripheral neural structure 614 from the signal 610 received at thesignal input structure 192, and generate a chemical blocking agentcontrol signal 618 for driving delivery of a chemical blocking agent620. Chemical blocking agent may reversibly block conduction in theperipheral neural structure 614 of the subject during at least a portionof the first activity state. As shown in FIG. 11A, and in greater detailin the expanded view of FIG. 11B, chemical blocking agent source 160 maybe configured to be positioned beneath at least a portion 612 of thebody of the subject 606 and to deliver a chemical blocking agent 620responsive to the chemical blocking agent control signal 618. Chemicalblocking agent source 160 may include anode 630, with associatedmicroneedle array 632 and chemical blocking agent reservoir 634, andcathode 636, with associated microneedle array 638 and electrolytereservoir 640. Microneedles in microneedle arrays 632 and 638 passthrough clothing 642 and stratum corneum 644 to permit delivery ofchemical blocking agent 620 to subject 606. Chemical blocking agentsource 160 may be configured to be located in or on a chair 604, asdepicted in FIG. 11.

FIG. 12A depicts an embodiment of a neural modulation system 100 inwhich a chemical blocking agent source 160 is located in a bed 650 uponwhich the subject 652 lies. FIG. 12B shows a portion of the system ofFIG. 12A in greater detail. In the embodiment of FIGS. 12A and 12B, asubject 652 rests on a bed 650. Chemical blocking agent source 160 ispositioned below a portion 656 of the body of subject 652. In thepresent example, chemical blocking agent source 160 includes pad 668impregnated with chemical blocking agent. Multiple ultrasoundtransducers 670 serve to cause movement of chemical blocking agentthrough the skin of subject 652. Ultrasound transducers 670 may be aimedand focused so that acoustic pulses produce constructive interference tomaximize acoustic energy at the areas of overlap. The general approachused in the system of FIGS. 12A and 12B is described in Saliba, S.,Mistry, D. J., Perrin, D. H., Gieck, J., and Weltman, A. “Phonophoresisand the absorption of dexamethasone in the presence of an occlusivedressing.” J. Athletic Training. 2007 Vol. 43, No. 3, pp. 349-354, whichis incorporated herein by reference in its entirety.

User input device 658 (in this example, a switch device including apush-button 660 that may be depressed by subject 652 to indicate thebeginning and end of a rest period) provides a signal 662 to signalprocessing portion 110 on cable 666, via signal input structure 192,representing the activity state of the subject. As described inconnection with other embodiments, signal processing portion 110controls delivery of a chemical blocking agent by chemical blockingagent source 160.

As an alternative to transdermal delivery, in some embodiments areversible conduction block may be produced in a peripheral neuralstructure of a subject with a chemical blocking agent source implantedwithin the body of the subject. An implantable chemical blocking agentsource has been shown in schematic form in FIG. 4. Implantable devicesmay include, but are not limited to, polymeric structures, infusionpumps, or MEMS devices, or various other implantable delivery devices asare known to those of skill in the art. Implantable devices may be usedto deliver chemical blocking agents systemically or locally to aspecific site of action.

A chemical blocking agent may be delivered using an implantable deliverydevice that includes an infusion pump that actively moves the chemicalblocking agent from an associated reservoir into a subject. FIG. 13depicts an embodiment of a neural modulation system 100 in which achemical blocking agent source 160 is implanted within the body of thesubject 708, while signal processing portion 110 is located external tothe body of the subject 708. Neural modulation system 100 as depicted inFIG. 13 includes signal input structure 192 configured to receive asignal 704 indicative of an activity state of at least a portion 706 ofa body of a subject 708 innervated by a peripheral neural structure 710.Signal processing portion 110 is configured to distinguish a firstactivity state of the at least a portion 706 of the body of the subject708 innervated by the peripheral neural structure 710 from a secondactivity state of the at least a portion 706 of the body of the subject708 innervated by the peripheral neural structure 710 from signal 704received at the signal input structure 192, and generate a chemicalblocking agent control signal 714 for driving delivery of a chemicalblocking agent 716, to reversibly block conduction in the peripheralneural structure 710 of subject 708 during at least a portion of thefirst activity state, and chemical blocking agent source 718. Chemicalblocking agent source 718 is configured to be implanted within the bodyof the subject 708 and to deliver a chemical blocking agent 716responsive to the chemical blocking agent control signal 714. In thisexample, chemical blocking agent source 718 includes reservoir 730containing chemical blocking agent 716 and pump 732, which pumpschemical blocking agent 716 through cannula 734 to the vicinity ofperipheral neural structure 710 (here, a nerve) under the control ofchemical blocking agent control signal 714. Pump 732 may be driven by apower source within or external to the body of the subject, via a wiredor wireless connection (see, e.g. US 2006/0190053, which is incorporatedherein by reference in its entirety).

A variety of types of pumps may be incorporated into an implantabledelivery systems such as, for example, a piston pump, rotary vane pump,osmotic pump, Micro Electro Mechanical Systems (MEMS) pump, diaphragmpump, peristaltic pump, or solenoid piston pump. For example, theinfusion pump may be a vapor-pressure powered pump in which afluorocarbon charging fluid such as freon is used to drive the pump as avapor-liquid mixture at normal body temperature and atmosphericpressure. Alternatively, the infusion pump may be a battery poweredperistaltic pump. The latter is exemplified by an intrathecal drugdelivery device in which an infusion pump with a controllable receiverunit is implanted under skin and a catheter is fed into the target site,in this case the spine (see, e.g., Belverud, S., Mogilner, A., Schulder,M. “Intrathecal Pumps.” Neurotherapeutics. 2008 Vol. 5, No. 1., pp.114-122, which is incorporated herein by reference in its entirety). Thereservoir associated with the pump may be refillable via percutaneousinjection. An external controller may be used to wirelessly control thepump.

In some cases, methods of modulating neural activity as describedherein, and as outlined, e.g. in FIG. 5, the step of producing areversible conduction block in a peripheral neural structure of asubject with a chemical blocking agent while the subject is in a firstactivity state may include delivering the chemical blocking agent in aninactive form non-specifically relative to the peripheral neuralstructure and delivering an activating energy to the peripheral neuralstructure or vicinity thereof to convert the chemical blocking agentfrom the inactive form to an inactive form. That is, the inactive formof the chemical blocking agent may be delivered systemically by variousmethods, as known to those of ordinary skill in the art, or the inactiveform may be delivering a portion of the body of the subject thatincludes the peripheral neural structure, but not in a finely targetedmanner. Various types of activating energy may be delivered in atargeted fashion, including but not limited to thermal energy, acousticenergy, electromagnetic energy, optical energy, and applied electricalfield, or an applied magnetic field.

External control of an implantable delivery device may be mediated byremote control through an electromagnetic wireless signal such as, forexample, infrared or radio waves that are able to trigger an electricalstimulus within the implanted device. Examples of remote control drugdelivery devices are described in U.S. Pat. Nos. 5,928,195; 6,454,759;and 6,551,235, which are incorporated herein by reference in theirentirety. Delivery of a chemical blocking agent may be initiated inresponse to an “on” trigger and stopped in response to an “off” trigger,for example. Alternatively, a chemical blocking agent may be deliveredas a microbolus, for example, in response to an “on” trigger asdescribed in U.S. Pat. No. 6,554,822, which is incorporated herein byreference in its entirety. External control may be initiated by acaregiver. In some cases, a subject may initiate delivery of thechemical blocking agent. As such, the system may have a built inmechanism to limit the number of allowable doses by a subject and/orcaregiver in a given time frame as described, for example, in U.S. Pat.No. 6,796,956, which is incorporated herein by reference in itsentirety.

In the example of FIG. 13, chemical blocking agent source 716 isimplanted, but the neural modulation system 100 includes an externalportion 726, which may be worn on the wrist in a manner similar to awristwatch. In the embodiment of FIG. 13, external portion 726 includessignal processing portion 110 and sensor 728, a motion sensor whichdetects movement of portion 706 of the body of subject 708, andgenerates signal 704, which is provided to signal input structure 192,as discussed above.

FIG. 14 depicts a related method, which includes the steps of producinga reversible conduction block in a peripheral neural structure of asubject with a chemical blocking agent while the subject is in a firstactivity state at 200; reversing the reversible conduction block in theperipheral neural structure of the subject to permit conduction in theperipheral neural structure when the subject is in a second activitystate at 202; wherein the method further includes reversing thereversible conduction block in the peripheral neural structure of thesubject to permit conduction in the peripheral neural structure when thesubject is in a second activity state by removing a chemical blockingagent used to produce the reversible conduction block in the peripheralneural structure of the subject, as indicated at 754; and repeating thesteps of producing a reversible conduction block in a peripheral neuralstructure of a subject with a chemical blocking agent while the subjectis in a first activity state and reversing the reversible conductionblock in the peripheral neural structure of the subject to permitconduction in the peripheral neural structure when the subject is in asecond activity state, as indicated at 204.

In the method of FIG. 14, chemical blocking agent is removed. A chemicalblocking agent may be removed by discontinuing delivery of chemicalblocking agent and permitting the chemical blocking agent to be removedthrough a naturally occurring process within the body of the subject(i.e., by permitting the concentration of chemical blocking agent at theperipheral neural structure to decrease through naturally occurringprocesses), e.g. by degradation or metabolism of the chemical blockingagent, dispersal, diffusion, or transport of the chemical blocking agentaway from the peripheral neural structure that is to be blocked, oruptake or binding of the chemical blocking agent by tissue.Alternatively, the chemical blocking agent may be removed by a furtherintervention or action, typically by the introduction of a material(chemical compound or mixture) or energy (including but not limited tolight, heat, acoustic energy, electromagnetic radiation, an electricalfield, a magnetic field) to the peripheral neural structure or vicinitythat causes or influences modification, degradation, metabolism,dispersal, diffusion, transport, uptake, or binding of the chemicalblocking agent so that it is no longer effective or available to produceblocking of conduction in the peripheral neural structure. In somecases, the chemical blocking agent may be removed by removing energyfrom the peripheral neural structure or its vicinity (e.g., by cooling),rather than delivering energy to the peripheral neural structure or itsvicinity. Removal of a chemical blocking agent by the introduction ofmaterial or energy may also be referred to as “reversal” of blocking andthe introduced material or energy may be termed a “reversing stimulus.”

FIG. 15 illustrates a neural modulation system 100 that includes asignal input structure 192 configured to receive a signal 760 indicativeof an activity state of at least a portion 762 of a body of a subjectinnervated by a peripheral neural structure 764. Neural modulationsystem 100 also includes a signal processing portion 110 configured todistinguish a first activity state of the at least a portion 762 of thebody of the subject innervated by the peripheral neural structure 764from a second activity state of the at least a portion 762 of the bodyof the subject innervated by the peripheral neural structure 764 fromthe signal 760 received at the signal input structure 192, and generatea chemical blocking agent control signal 766 for driving delivery of achemical blocking agent 768 adapted to reversibly block conduction inthe peripheral neural structure 764 of the subject during at least aportion of the first activity state. In some embodiments, as disclosedelsewhere herein, discontinuation of generation of chemical blockingagent control signal may stop release of chemical blocking agent 768. Asindicated in FIG. 15, the signal processing portion may optionallygenerate a release stimulus control signal 770 for controllingdiscontinuation of delivery of the chemical blocking agent 768 when thesubject is in the second activity state. Neural modulation system 100further includes sensor 772, which is operatively connected to thesignal input structure 192 and configured to generate the signal 760indicative of an activity state of at least a portion 762 of a body of asubject innervated by a peripheral neural structure 764 responsive to anactivity of the at least a portion 762 of the body of the subject, and achemical blocking agent source 160 configured to deliver a chemicalblocking agent 768 responsive to the chemical blocking agent controlsignal. A release stimulus control signal 770 may be delivered to thechemical blocking agent source 160 from the signal processing portion110 on the same line or channel as the chemical blocking agent controlsignal 766, or it may be provided on a separate line or channel.

The signal processing portion may be configured to repetitively generatethe chemical blocking agent control signal for driving delivery of achemical blocking agent adapted to reversibly block conduction in theperipheral neural structure of the subject during at least a portion ofthe first activity state and the release stimulus control signal forcontrolling discontinuation of delivery of the chemical blocking agentwhen the subject is in the second activity state.

In some embodiments, the signal processing portion may be configured torepetitively generate the chemical blocking agent control signal fordriving delivery of a chemical blocking agent adapted to reversiblyblock conduction in the peripheral neural structure of the subjectduring at least a portion of the first activity state and the releasestimulus control signal for controlling discontinuation of delivery ofthe chemical blocking agent when the subject is in the second activitystate over a period of time sufficient to produce modulation of animmune response in a region innervated by the peripheral neuralstructure. Modulation of immune response may be assessed according tomethods as discussed elsewhere herein.

In some embodiments, the signal processing portion may be configured togenerate the chemical blocking agent control signal for driving deliveryof a chemical blocking agent adapted to reversibly block conduction inthe peripheral neural structure of the subject during at least a portionof the first activity state and the release stimulus control signal forcontrolling discontinuation of delivery of the chemical blocking agentwhen the subject is in the second activity state cyclically, whereineach cycle includes a blocking period during which a chemical blockingagent sufficient to produce reversible conduction block in a peripheralneural structure of a subject is produced while the subject is in afirst activity state and a release period during which no chemicalblocking agent is delivered, e.g., as illustrated in FIG. 6.

The signal processing portion may be configured to generate the chemicalblocking agent control signal for driving delivery of a chemicalblocking agent adapted to reversibly block conduction in the peripheralneural structure of the subject during at least a portion of the firstactivity state and the release stimulus control signal for controllingdiscontinuation of delivery of the chemical blocking agent when thesubject is in the second activity state cyclically at a rate of onecycle per day.

The signal processing portion may be configured to generate the chemicalblocking agent control signal for driving delivery of a chemicalblocking agent adapted to reversibly block conduction in the peripheralneural structure of the subject during at least a portion of the firstactivity state and generate the release stimulus control signal forcontrolling discontinuation of delivery of the chemical blocking agentwhen the subject is in the second activity state in alternationaccording to a pre-set schedule.

Repetitive or cyclical generation of blocking stimuli may be performedas described herein, under the control of software, hardware, or otherelectrical circuitry by methods known to those of skill in the art.

As shown in FIG. 16, a method of modulating neural activity may includeproducing a reversible conduction block in a peripheral neural structureof a subject with a chemical blocking agent while the subject is in afirst activity state (step 800), reversing the reversible conductionblock in the peripheral neural structure of the subject to permitconduction in the peripheral neural structure when the subject is in asecond activity state by applying a reversing stimulus configured tocounter the chemical blocking agent used to produce the reversibleconduction block in the peripheral neural structure of the subject (step802), and repeating the steps of producing a reversible conduction blockin a peripheral neural structure of a subject while the subject is in afirst activity state and reversing the reversible conduction block inthe peripheral neural structure of the subject to permit conduction inthe peripheral neural structure when the subject is in a second activitystate (step 804).

A reversing stimulus may be any stimulus sufficient to counter thechemical blocking agent and return the nerve to a normally conductivestate. A reversing stimulus may be a chemical reversing agent or areversing stimulus may be a non-chemical agent (e.g., an electricalfield, a magnetic field, an acoustic stimulus, a thermal stimulus, or anelectromagnetic stimulus). The reversing stimulus may cancel or opposethe effect of the chemical blocking agent. For example, chemicalreversing agent may cause or influence modification, degradation,metabolism, dispersal, diffusion, transport, uptake, or binding of thechemical blocking agent to oppose the effect of the chemical blockingagent. The chemical reversing agent may reverse the effect of thechemical blocking agent by influencing the same or different cellularmechanisms as the chemical blocking agent, to restore or unblockconduction in the peripheral neural structure. A chemical reversingagent may be delivered with either the same chemical agent source as thechemical blocking agent, or with a different source.

FIG. 17 illustrates an embodiment of a neural modulation system 100 thatincludes separate chemical blocking agent source 160 and reversingstimulus source 874. Neural modulation system 100 includes a signalinput structure 192 configured to receive a signal 854 indicative of anactivity state of at least a portion 856 of a body of a subjectinnervated by a peripheral neural structure 860, signal processingportion 110, chemical blocking agent source 160, and reversing stimulussource 874. Signal processing portion 110 may be configured todistinguish a first activity state of the at least a portion 856 of thebody of the subject innervated by the peripheral neural structure 860from a second activity state of the at least a portion 856 of the bodyof the subject innervated by the peripheral neural structure 860 fromsignal 854 received at signal input structure 192, generate chemicalblocking agent control signal 864 for driving delivery of a chemicalblocking agent 866 to reversibly block conduction in the peripheralneural structure 860 of the subject during at least a portion of thefirst activity state, and generate a reversing stimulus control signal868 for driving production of a reversing stimulus 870 to counterchemical blocking agent 866 used to produce the reversible conductionblock in the peripheral neural structure 860 of the subject. A chemicalblocking agent source 160 may be configured to deliver a chemicalblocking agent 866 responsive to the chemical blocking agent controlsignal 864, and a reversing stimulus source 874 may be configured toproduce a reversing stimulus 870 responsive to the reversing stimuluscontrol signal 868.

As noted previously, the action of a primary chemical blocking agent maybe reversed by the addition of a chemical reversing agent. In someinstances, the chemical reversing agent may be an antagonist thatcompetes with the agonist chemical blocking agent at the active site onthe neuromuscular target, resulting in a decrease in the response to thechemical blocking agent. For example, the nerve blocking activity of anopioid receptor agonist such as, for example, morphine may be reversedby an opioid antagonist such as, for example, nalmefene, naloxone, andnaltrexone. Naloxone, for example, has been used to treat acute opioidoverdose as well as the adverse effects associated with intravenous orepidural opioids during and post surgical intervention (Basic andClinical Pharmacology, 10^(th) Edition. 2007; edited by Bertram Katzung,McGraw Hill Medical, New York, N.Y., which is incorporated herein byreference in its entirety). As another example, the benzodiazepineantagonist flumazenil may be used to reverse the effects of abenzodiazepine such as diazepam, lorazepam or midazolam. The prolongedaction of a local anesthetic such as lidocaine in combination with analpha adrenergic receptor agonist such as epinephrine or norepinephrinemay be reversed by adding an alpha adrenergic receptor antagonist suchas phentolamine, phentolamine hydrochloride, phentolamine mesylate,tolazoline, yohimbine, rauwolscine, doxazosin, labetolol, prazosin,tetrazosin and trimazosin as described in U.S. Pat. No. 6,764,678, whichis incorporated herein by reference in its entirety. Alternatively, thechemical reversing agent may be an agonist that competes with theantagonist chemical blocking agent, resulting in a decrease in responseto the chemical blocking agent. For example, a beta agonist such asisoproterenolol may be used to reverse the effects of a beta blocker. Insome instances, the action of a chemical blocking agent such as a localanesthetic may be reversed using an inorganic or organic salt solutionwith a pH of 7 or higher as described in U.S. Pat. No. 5,192,527, whichis incorporated herein by reference in its entirety.

The reversing stimulus may be any type of stimulus that serves toreverse the effect of the chemical blocking agent to bring the neuralstructure back to (or toward) its previous conductivity state. In someembodiments, the reversing stimulus source may be a chemical agentsource generally of the same type as the chemical blocking agent source.In some embodiments, the reversing stimulus source may include at leasta portion of the chemical blocking agent source, while in otherembodiments, the reversing stimulus source may be a different orseparate stimulus source of the same type as the chemical blocking agentsource. In some embodiments, the reversing stimulus source may include adifferent type of stimulus source than the chemical blocking agentsource. For example, the reversing stimulus source may include one ormore of a magnetic field source, an electric field source, anelectromagnetic transducer, an optical photon source, an acoustic energysource, a heat source or a cooling source.

Applying a reversing stimulus to counter the chemical blocking agentused to produce the reversible conduction block in the peripheral neuralstructure of the subject may include applying an electric or magneticfield to at least a portion of the peripheral neural structure. Theelectric or magnetic field used as a reversing stimulus may be a pulsedelectric or magnetic field delivered to at least a portion of theperipheral neural structure, or it may be cyclical or time-varyingelectric or magnetic field.

In some embodiments, applying a reversing stimulus to counter thechemical blocking agent used to produce the reversible conduction blockin the peripheral neural structure of the subject may include applyingelectromagnetic energy to at least a portion of the peripheral neuralstructure. Applying a reversing stimulus to counter the chemicalblocking agent used to produce the reversible conduction blocking in theperipheral neural structure of the subject may include heating orcooling at least a portion of the peripheral neural structure.

FIG. 18 shows a further extension of the method of modulating neuralactivity outlined in FIG. 5. The method includes producing a reversibleconduction block in a peripheral neural structure of a subject with achemical blocking agent while the subject is in a first activity state(step 200), reversing the reversible conduction block in the peripheralneural structure of the subject to permit conduction in the peripheralneural structure when the subject is in a second activity state (step202), repeating the steps of producing a reversible conduction block ina peripheral neural structure of a subject with a chemical blockingagent while the subject is in a first activity state and reversing thereversible conduction block in the peripheral neural structure of thesubject to permit conduction in the peripheral neural structure when thesubject is in a second activity state (step 204), determining thatproducing the reversible conduction block in the peripheral neuralstructure of the subject with a chemical blocking agent while thesubject is in a first activity state results in a desired effect in thesubject (step 906), and producing a non-reversible conduction block inthe peripheral neural structure of the subject (step 908). A desiredeffect may be, for example, reduction or elimination of pain, undesiredsensations, inflammation, immunological or physiological problems causedor contributed to by peripheral neural activity in the blockedperipheral neural structure. Determination that a desired effect hasbeen produced may be made through sensing of various physiological orphysical parameters, or by qualitative or subjective reporting obtainedfrom the subject.

A non-reversible conduction block may be produced in various ways. Asshown in further detail in FIG. 19, a method including steps 200, 202,204, 906 and 908 (as described in connection with in FIG. 18) mayinclude producing a non-reversible conduction block by applying heat toat least a portion of the peripheral neural structure of the subject (asindicated at 910), for example with a Peltier device. Various othertechniques can be used to apply heat, without limitation, as are knownto those of skill in the art. Some examples include: electrical current,optical photons, ultrasound, the use of a resistive heater, anexothermic reaction device, etc. . . . See, for example, U.S. PublishedPatent Application 2005/0288730, which is incorporated herein byreference. Heat may cause non-reversible conduction block by variousmechanisms, e.g. chemical ablation of tissue or stimulation ofapoptosis. See, for example, the method as disclosed in U.S. Pat. No.6,405,732, which is incorporated herein by reference in its entirety.The present method is not limited to any particular mechanism ofproducing a non-reversible conduction block through application of heat.A non-reversible conduction block may be produced by cooling or removingheat from at least a portion of the peripheral neural structure of thesubject (as indicated at 912), for example with a Peltier device, fluidheat transfer device, or endothermic reaction device; applying anelectrical current to at least a portion of the peripheral neuralstructure of the subject (as indicated at 914); delivering acousticenergy to at least a portion of the peripheral neural structure of thesubject (as indicated at 916); delivering photons to at least a portionof the peripheral neural structure of the subject (as indicated at 918);delivering a chemical agent (e.g. capsaicin) to at least a portion ofthe peripheral neural structure of the subject (as indicated at 920); orby surgical transection of at least a portion of the peripheral neuralstructure of the subject (as indicated at 922).

Producing a reversible conduction block may include producingsubstantially complete blockage of conduction in the peripheral neuralstructure of the subject. Alternatively, in some cases only partialblockage of conduction may be obtained, e.g. as depicted in FIGS. 2E and2F. Completeness of blockage may be assessed by measuring neuralactivity by known methods, e.g., by delivering a well-defined stimuluson one side of the blocked region and measuring the evoked neuralactivity on the other side of the blocked region and, optionally,comparing the evoked activity to activity measured at the same siteprior to blocking of conduction or at an location upstream of the block,either before or after blocking.

FIG. 20 depicts a further embodiment of a neural modulation system thatis similar to previously described systems, but in addition includes anon-reversible blocking source. The upper portion of FIG. 20 includes ablock diagram of system 100, while the lower portion illustrates system100 in situ in an appendage of a subject. Neural modulation system 100may include signal input structure 192 configured to receive signal 929indicative of an activity state of at least a portion 931 of a body of asubject innervated by a peripheral neural structure 935, and a signalprocessing portion 110 configured to distinguish a first activity stateof the at least a portion 931 of the body of the subject innervated bythe peripheral neural structure 935 from a second activity state of theat least a portion 931 of the body of the subject innervated by theperipheral neural structure 935 from signal 929 received at signal inputstructure 192. Signal 929 may be carried on line 925, as shown in theexpanded view at the bottom of FIG. 20. Signal processing portion isfurther configured to generate a chemical blocking agent control signal939 for driving delivery of a chemical blocking agent adapted toreversibly block conduction in the peripheral neural structure 935 ofthe subject during at least a portion of the first activity state,determine that producing the reversible conduction block in peripheralneural structure 935 of the subject while the subject is in a firstactivity state results in a desired effect in the subject, and generatea non-reversible blocking source control signal 941. Neural modulationsystem 225 also includes chemical blocking agent source 160 configuredto deliver a chemical blocking agent responsive to the chemical blockingagent control signal 939, and a non-reversible blocking source 943.Chemical blocking agent source 160 includes a plurality of chemicalblocking agent reservoirs 953 distributed circumferentially aroundperipheral neural structure 935. Non-reversible blocking source controlsignal 941 drives non-reversible blocking source 943 to perform anaction adapted for producing a non-reversible conduction block inperipheral neural structure 935 of the subject. Non-reversible blockingsource control signal 941 is also carried on line 925, shown in theexpanded view in the lower portion of FIG. 20. Non-reversible blockingsource 943 may be configured to perform an action adapted for producinga non-reversible conduction block in the peripheral neural structure ofthe subject responsive to the non-reversible blocking source controlsignal 941. In the example shown in FIG. 20, non-reversible blockingsource 943 is an electrode which can function as a heating element andwhich may also be used for sensing neural activity from peripheralneural structure 935. The sensed neural activity may be provided assignal 929 to signal input structure 192 on line 925, to serve as asource of information regarding activity of the portion 931 of the bodyof the subject innervated by peripheral neural structure 935, which inthe present example is the region of joint 957 in body portion 931.Non-reversible blocking source 943 may be configured to produce thermalablation of at least a portion of the peripheral neural structure of thesubject, or to stimulate apoptosis in the peripheral neural structure,for example. The practice of the invention is not limited to anyparticular mechanism for producing non-reversible blocking.Alternatively, a heat source may include, but is not limited to, anappropriately configured Peltier device, a light source, a fluidheat-transfer device, an exothermic reaction device, or an acousticelement.

In other embodiments, the non-reversible blocking source may include acooling source, such as an appropriately configured Peltier device or areservoir containing a chemical composition or mixture capable ofundergoing a controllable endothermic reaction. In other embodiments,the non-reversible blocking source may include an electrical currentsource, and acoustic energy source, a photon source, or a chemicalblocking agent source. In general, a non-reversible blocking source maybe any source of any type of energy, material, or action sufficient todamage or destroy the peripheral neural structure to produce permanent(or substantially permanent) blockage of nerve conduction. As a furtherexample, in some embodiments, the non-reversible blocking source mayinclude a surgical transection mechanism.

In some embodiments, a chemical blocking agent source may be configuredto produce a spatially varying chemical blocking stimulus. A spatiallyvarying chemical blocking stimulus may be produced, for example, by achemical blocking agent source that includes a plurality of spatiallydistributed chemical agent sources, which may be distributedcircumferentially around the nerve, as depicted in FIG. 20, or in otherdistributions, including but not limited to, a longitudinal distributionalong the nerve or an array disposed over or around the nerve. Aplurality of spatially distributed chemical agent sources may include aplurality of stimulus sources all of the same type, or may includedifferent types of chemical agent sources. In some cases, a plurality ofspatially distributed chemical agent sources may deliver different typesof chemical agents.

FIG. 21 illustrates a further variant of a method of modulating neuralactivity, which may include producing a reversible conduction block of asubset of nerve fibers in a peripheral neural structure of a subjectwith a chemical blocking agent while the subject is in a first activitystate (step 950), reversing the reversible conduction block of thesubset of nerve fibers in the peripheral neural structure of the subjectto permit conduction in the subset of nerve fibers in the peripheralneural structure when the subject is in a second activity state (step952), and repeating the steps of producing a reversible conduction blockin the subset of nerve fibers in a peripheral neural structure of asubject with a chemical blocking agent while the subject is in a firstactivity state and reversing the reversible conduction block in thesubset of nerve fibers in the peripheral neural structure of the subjectto permit conduction in the subset of nerve fibers in the peripheralneural structure when the subject is in a second activity state (step954). In different variations of the method (indicated with dashed boxesin FIG. 21) the subset of nerve fibers in the peripheral neuralstructure of the subject may include nerve fibers within a selecteddiameter range, as indicated at 956, within a selected spatialdistribution within the peripheral neural structure, as indicated at958, within selected fascicles and/or within the peripheral neuralstructure, as indicated at 960, based upon location of delivery ofchemical agent or differential sensitivity of different diameter fibersto chemical blocking agents.

Alternatively, or in addition, the subset of nerve fibers in theperipheral neural structure of the subject may include nerve fibersincluding a selected molecular feature (as indicated at 962). Selectiveblocking of nerve fibers having particular molecular features has beendescribed in Binshtok, A. M.; Bean, B. P. and Woolf, C. J.; “Inhibitionof nociceptors by TRPV1-mediated entry of impermeant sodium channelblockers”; Nature, Vol. 449, 2007; pp. 607-611; doi:10.1038/nature06191and McCleskey, E. M. “A local route to pain relief”; Nature; Vol. 449;2007; pp. 545-546, which are incorporated herein by reference.Responsiveness of nerve fibers having selected molecular features tochemical blocking agents may be modulated, for example, by materialstargeted to nerve fibers having the molecular feature. A variety ofmolecular markers for specific types of nerve fibers are known. Forexample, neurofilament (NF) is a highly specific marker for myelinatednerve fibers; substance P and calcitonin gene-related protein (CGRP) aremarkers for sensory nerve fibers (both A and c-type); Acetylcholine(Ach) is a marker for cholinergic nerve fibers, which may be sympatheticpre-ganglionic fibers or parasympathetic pre-ganglionic orpost-ganglionic fibers; tyrosine hydroxylase (TH) is specific foradrenergic nerve fibers (sympathetic postganglionic neurons). Forexample, see Tokushige, N.; Markham, R.; Russell, P. and Fraser, I. S.;“Nerve fibres in peritoneal endometriosis”; Human Reproduction; 2006;Vol. 21; No. 11; pp. 3001-3007, which is incorporated herein byreference in its entirety. Cyclin dependent kinase 5 (Cdk5) is expressedin nociceptive fibers (Pareek, T. K.; Keller, J.; Kesavapany, S.; Pant,H. C.; Iadarola, M. J.; Brady, R. O.; and Kulkarni, A. B.;“Cyclin-dependent kinase 5 activity regulates pain signaling”; PNAS;Jan. 17, 2006; Vol. 103, No. 3; pp. 791-796), incorporated herein byreference in its entirety. Similarly, capsaicin receptor (vanilloidreceptor type 1 (VR1) and variants thereof, e.g. vanilloid receptorhomologue (VRL1) are expressed in A and C fiber sensory neurons, asdescribed in Ma, Q.-P.; “Vanilloid receptor homologue, VRLI, isexpressed by both A- and C-fiber sensory neurons”; Neuro Report; Vol.12, No. 17; 4 Dec. 2001; pp. 3693, which is incorporated herein byreference in its entirety.

In some embodiments of a neural modulation system, a chemical blockingagent source may be configured to produce substantially completeblockage of conduction in the peripheral neural structure of the subjectresponsive to the chemical blocking agent control signal. In otherembodiments, a chemical blocking agent source may be configured toproduce blockage of a subset of nerve fibers in the peripheral neuralstructure of the subject responsive to the chemical blocking agentcontrol signal, based, for example, upon approaches as described above.The subset of nerve fibers in the peripheral neural structure of thesubject may include nerve fibers within a selected diameter range, nervefibers within a selected spatial distribution within the peripheralneural structure, or nerve fibers including a selected molecularfeature.

FIGS. 22A-22C depict examples of chemical blocking agent sources 160that may be used in neural modulation systems as described and depictedgenerally herein.

In FIG. 22A, chemical blocking agent source 160 is an infusion pump1000, similar to that depicted in FIG. 13, but configured to deliver twochemical agents. Infusion pump 1000 includes reservoir 1002 containing afirst chemical agent and reservoir 1004 containing a second chemicalagent. Chemical agents are driven from reservoirs 1002 and 1004 by pumps1006 and 1008, respectively, under the control of one or more controlsignals 1010 and 1012, which may be provided to pumps 1006 and 1008 froma controller (not shown) via either leads 1014 and 1016 as depicted inFIG. 22A, or, alternatively, via a wireless connection. First and secondchemical agents are delivered in the vicinity of peripheral neuralstructure 1018 through first lumen 1020 and second lumen 1022,respectively of dual lumen catheter 1024.

In some embodiments, a neural modulation system may deliver acombination of chemical blocking agent components. The components may bedelivered from a single chemical blocking agent source, or,alternatively, from multiple sources. For example, the infusion pump1000 depicted in FIG. 22A may be used in such a system. Such a systemmay include a primary chemical blocking agent source configured todeliver a primary chemical blocking agent component and a secondarychemical blocking agent source configured to deliver a secondarychemical blocking agent component. The primary chemical blocking agentcomponent and the secondary chemical blocking agent component acttogether to reversibly block conduction in the peripheral neuralstructure. For example, referring to FIG. 22A, the signal processingportion (not shown) may be configured to generate a chemical blockingagent control signal including a primary chemical blocking agent controlsignal 1010 for driving delivery of the primary chemical blocking agentcomponent (from reservoir 1002) and a secondary chemical blocking agentcontrol signal 1012 for driving delivery of the secondary chemicalblocking agent component (from reservoir 1004).

Producing a reversible conduction block in a peripheral neural structureof a subject with a chemical blocking agent may include delivering aprimary chemical blocking agent component and delivering a secondarychemical blocking agent component, wherein the primary chemical blockingagent component and the secondary chemical blocking agent component acttogether to reversibly block conduction in the peripheral neuralstructure.

A primary chemical blocking agent may be used in combination with one ormore secondary chemical blocking agents. Primary and secondary chemicalblocking agents may have the same method of action such as, for example,two or more opiates. Alternatively, the primary and secondary chemicalblocking agents may have different methods of action such as one or moreopioid agonist in combination, for example, with a local anesthetic, anNSAID, and/or a benzodiazepine. For example, a primary chemical blockingagent such as the opiate hydrocodone might be used in combination with asecondary chemical blocking agent such as the NSAID ibuprofen asexemplified by the therapeutic combination drug Vicoprofen. Similarly, asodium channel blocker such as tetrodotoxin or saxitoxin may be used incombination with a local anesthetic, vasoconstrictor, glucocorticoid,alpha agonist (e.g., epinephrine, phenylephrine), beta-blockers (e.g.,propranalol), and mixed central-peripheral alpha-2 agonists (e.g.,clonidine) to enhance the neural blockade as described in U.S. Pat. No.6,326,020, which is incorporated herein by reference in its entirety.

A chemical blocking agent may be delivered using an implantable deliverydevice or system that incorporates a MEMS (Micro Electro MechanicalSystems) fabricated microchip. Examples of MEMS and/or microfabricateddevices for potential delivery of a therapeutic agent are described inU.S. Pat. Nos. 5,993,414; 6,454,759; and 6,808,522, which areincorporated herein by reference in their entirety. The MEMS implantabledelivery method may have one or more microfabricated drug reservoirssuch as, for example, microparticle reservoirs, silicon microarrayreservoirs, and/or polymer microreservoirs as described by Grayson, A.C. R, Shawgo, R. S., Johnson, A. M., Flynn, N. T., Yawen, L., Cima, M.J., and Langer, R. “A bioMEMS review: MEMS technology forphysiologically integrated devices.” Proceedings of the IEEE, 2004, Vol.92, No. 1, pp. 6-21, which is incorporated herein by reference in itsentirety. Microparticles fabricated from silicon may be used thatcontain an internal space which is loaded with drug using amicroinjector and capped, for example, with a slow dissolving gelatin orstarch. Polymer microreservoirs may be fabricated by micromoldingpoly(dimethylsiloxane) or by patterning in multilayer poly(D-lacticacid) and (vinyl alcohol), for example. In some instances, the polymermicroreservoirs may be capped with polymers that degrade at variousrates in vivo depending upon the length of the polymer, allowing forcontrolled release of multiple doses. Alternatively, an array ofmicroreservoirs on a microchip may be used in which each dose ofchemical blocking agent is contained in its own reservoir and capped byan environmentally sensitive material. For example, the microreservoirsmay be capped with a gold membrane which is weakened and ruptured byelectrochemical dissolution in response to application of an anodevoltage to the membrane in the presence of chloride ions, resulting inrelease of drug as described in U.S. Pat. No. 5,797,898 and in Prescott,J. H., Lipka, S., Baldwin, S., Sheppard, N. F., Maloney, J. M., Coppeta,J., Yomtov, B., Staples, M. A., and Santini, J. T., “Chronic, programmedpolypeptide delivery from an implanted, multireservoir microchipdevice.” Nat. Biotech. 2006, Vol. 24, No. 4, pp. 437-438, which areincorporated herein by reference in their entirety. Alternatively, themicroreservoirs may be capped by a temperature sensitive material thatmay be ruptured in response to selective application of heat to one ormore of the reservoirs as described in U.S. Pat. No. 6,669,683, which isincorporated herein by reference in its entirety. Wireless induction ofa voltage or thermal trigger, for example, to a given reservoir of themicroarray by a subject would enable on-demand release of a chemicalblocking agent. Alternatively, the microchip array may incorporate asensor component that signals release of a chemical blocking agent by aclosed-loop mechanism in response to a chemical or physiological stateas described in U.S. Pat. No. 6,976,982, which is incorporated herein byreference in its entirety. FIG. 22B depicts a chemical blocking agentsource 160 that includes a cuff 1030 positioned around peripheral neuralstructure 1032 and includes a plurality of reservoirs 1034, eachcontaining a chemical blocking agent. Each reservoir may be separatelyaddressable by control lines 1036 and 1038, though in some cases it maybe desirable to control more than one reservoir with a single controlline.

In further embodiments, an implantable delivery device may incorporate apolymer or other matrix that releases a chemical blocking agent. Forexample, FIG. 22C illustrates a chemical blocking agent source 160 ofthis type. In FIG. 22C, polymeric matrix 1040 contains embeddedferromagnetic particles 1042 and chemical blocking agent 1044. Chemicalblocking agent 1044 may be released from polymeric matrix 1040 applyinga magnetic field to produce heating of ferromagnetic particles 1042, tocause polymeric matrix 1040 to release chemical blocking agent 1044 inthe vicinity of peripheral neural structure 1046. See for example,Hsieh, D. S. T., Langer, R., Folkman, J. “Magnetic modulation of releaseof macromolecules from polymers,” Proc. Natl. Acad. Sci. U.S.A., 1981,Vol. 78., No. 3., pp. 1863-1867, which is incorporated herein byreference in its entirety. Alternatively, in related embodiments, abiologically active compound may be formulated with a solid hydrophilicpolymer that swells by osmotic pressure after implantation, allowinginteraction with a solubilizing agent and release of the biologicallyactive compound through a non-porous rate-controlling membrane asdescribed in U.S. Pat. No. 5,035,891, which is incorporated herein byreference in its entirety.

In some instances, an implantable delivery system may incorporate anatural and/or synthetic stimulus-responsive hydrogel or polymer whichchanges confirmation rapidly and reversibly in response to environmentalstimuli such as, for example, temperature, pH, ionic strength,electrical potential, light, magnetic field or ultrasound (see, e.g.,Stubbe, B. G., De Smedt, S. C., and Demeester, J. “‘Programmed polymericdevices’ for pulsed drug delivery,” Pharmaceutical Res. 2004, Vol. 21,No. 10, pp. 1732-1740, which is incorporated herein by reference in itsentirety). Examples of polymers are described in U.S. Pat. Nos.5,830,207; 6,720,402; and 7,033,571, which are incorporated herein byreference in their entirety. In some instances, the chemical blockingagent to be delivered by the implantable delivery method may bedissolved or dispersed in the hydrogel or polymer. Alternatively, ahydrogel and/or other stimulus-responsive polymer may be incorporatedinto an implantable delivery device. For example, a hydrogel or otherpolymer or other smart material may be used as an environmentallysensitive actuator to control flow of a therapeutic agent out of animplantable device as described in U.S. Pat. Nos. 6,416,495; 6,571,125;and 6,755,621, which are incorporated herein by reference in theirentirety. As such, an implantable delivery device may incorporate ahydrogel or other polymer that modulates delivery of one or morechemical blocking agents in response to environmental conditions.

An implantable chemical blocking agent source as illustrated in FIGS.22A-22C, or alternatively, as described and depicted elsewhere herein,may be powered by a current source, which may be fully implantable.Alternatively, current may be supplied by via a wireless transcutaneouslink (e.g., as described in U.S. Pat. No. 7,236,822, which isincorporated herein by reference in its entirety). An implantable devicefor delivery of a chemical blocking agent may be powered by a standardlithium battery. In some instances, the battery may be rechargeable. Forexample, a battery associated with an implantable device may berecharged transcutaneously via inductive coupling from an external powersource temporarily positioned on or near the surface of the skin asdescribed in U.S. Pat. No. 7,286,880, which is incorporated herein byreference in its entirety. Alternatively, the energy source for animplantable device may come from within the subject. For example, animplantable device may be powered by conversion of thermal energy fromthe subject into an electrical current as described in U.S. Pat. No.7,340,304, which is incorporated herein by reference in its entirety.

The pattern of delivery of the chemical blocking agent may varyspatially as well as temporally, and in some embodiments it may varyboth spatially and temporally. A single neural modulation system asdepicted, for example, in FIGS. 22A and 22B may deliver chemicalblocking agents at multiple locations, and by varying the rate ofdelivery of chemical blocking agents from each chemical blocking agentsource, a spatially and/or time varying pattern of delivery may beproduced. Alternatively, multiple neural modulation systems, distributedspatially with regard to one or more peripheral neural structures may beused to produce a spatially varying delivery pattern in otherembodiments.

Various configurations and combinations of devices/structures fordelivering chemical agents may be used to produce conduction block bythe approaches described herein, and the invention is not limited to anyparticular type/configuration of chemical agent sources. In order tocontrol delivery of a chemical agent to produce either blocking orexcitation, a chemical agent source may be connected (via a wired orwireless connection) to an energy source such as an electrical currentor voltage source. Accordingly, the term “chemical agent source”, asused herein, is considered to include at least one supply of a chemicalagent and a mechanism for affecting delivery of the chemical agent, andmay also include one or more source of energy for enabling delivery ofthe chemical agent(s).

Methods of neural modulation as described herein may be implemented witha neural modulation system 100 as illustrated generally in FIG. 23,which depicts a variation of the system shown in FIG. 3. Basiccomponents of neural modulation system 100 include a signal inputstructure 192, sensor 1054, and signal processing portion 110. Signalinput structure 192 may be operatively connected to sensor 1054 andconfigured to receive a signal indicative of an activity state of atleast a portion of a body of a subject 1055 innervated by a peripheralneural structure. Signal input structure 192, and other signal inputstructures described elsewhere herein, may be of various typesconfigured to accept or receive signals of various types. Such signalinput structures are known to those of skill in the art, and mayinclude, but are not limited to, analog or digital inputs capable ofaccepting or receiving electrical, optical, acoustic, electromagnetic,or other types of signals. Signals may be accepted or received at asignal input structure through direct physical contact (e.g., anelectrical contact), or by reception of a signal transmitted through oracross a medium (e.g., via an inductive, optical, or electromagneticlink). Sensor 1054 may be operatively connected to the signal inputstructure 192 and configured to generate a signal indicative of anactivity state of a portion of the body of the subject 1055 innervatedby the peripheral neural structure responsive to an activity of theportion of the body. Signal processing portion 110 may be configured todistinguish a first activity state at least partially based on thesignal received by the signal input structure 192, and to generate achemical blocking agent control signal 1058 for driving delivery of achemical blocking agent 1060 by chemical blocking agent source 160.

FIG. 23 depicts in schematic form an embodiment of a neural modulationsystem 100, in which signal processing portion 110 and signal inputstructure 192 are packaged together in package 1066 and sensor 1054, andchemical blocking agent source 160 is packaged separately. In someembodiments, chemical blocking agent source 160 or portion thereof maybe located outside the body of the subject, and the chemical blockingagent may pass through the skin and underlying tissue to reach theneural structure that is to be blocked. In other embodiments, a chemicalblocking agent source may be positioned within the body of the subject,either permanently or temporarily. Suitable positioning of the chemicalblocking agent source will depend upon the type of chemical blockingagent source being used and the type and location of the neuralstructure to be blocked.

Neural modulation system 100 may optionally include override signalinput structure 1070, as indicated by the dashed box in FIG. 23.Override signal input structure 1070 may be configured to receive asignal indicative of a condition of the body of the subject, and signalprocessing portion 110 may be configured to override generation of thechemical blocking agent control signal 1058 responsive to a signalindicative of an override condition of the body of the subject onoverride signal input structure 1070. Alternatively, override signalinput structure 1070 may be configured to receive a signal indicative ofa condition external to the body of the subject, and signal processingportion 110 may be configured to override generation of the chemicalblocking agent control signal responsive to a signal indicative of anoverride condition external to the body of the subject on the overridesignal input. As a further alternative, or in addition, override signalinput structure 1070 may be configured to receive a signal from a userinput device, and the signal processing portion may be configured tooverride generation of the chemical blocking agent control signalresponsive to a signal indicative of a user override request on theoverride signal input. The override signal may indicate that it is nolonger desirable to apply the chemical blocking agent, for reasons ofsafety, comfort, or convenience, for example, and may be indicative of acondition of the body of the subject, or of a condition external to thebody of the subject (e.g., in the environment of the subject). If theoverride signal is detected from a user input device, it may be the sameuser input device used in normal operation of the system, and theoverride signal input structure may be the same as the signal inputstructure that normally receives input from a user input device.

Sensor 1054 as depicted generally in FIG. 23 (as well as sensors used inother embodiments depicted and/or described herein) may be any of avariety of different types of sensors, including, but not limited to,pressure sensors, force sensors, chemical sensors (including but notlimited to sensors capable of sensing pH, gas, ions, proteins, orbiomolecules), temperature sensors, electrical sensors (for sensingcurrent, potential, charge, resistance, resistivity, capacitance, orother electrical parameters), magnetic sensors, optical sensors, motionsensors, etc. A single sensor or multiple sensors, of the same ormultiple different types, may be used.

The signal processing portion 110, as depicted in FIG. 23, may beconfigured to determine the onset of the first activity state andgenerate the chemical blocking agent control signal for driving deliveryof a chemical blocking agent adapted to reversibly block conduction inthe peripheral neural structure of the subject at least intermittentlyresponsive to detecting the onset of a first activity state in thesubject. In some cases, the signal processing portion may be configuredto generate the chemical blocking agent control signal for drivingdelivery of a chemical blocking agent adapted to reversibly blockconduction in the peripheral neural structure of the subjectsubstantially immediately upon detecting the onset of the first activitystate in the subject. In other cases, the signal processing portion maybe configured to generate the chemical blocking agent control signal fordriving delivery of a chemical blocking agent adapted to reversiblyblock conduction in the peripheral neural structure of the subject at adelay interval after detecting the onset of the first activity state inthe subject. The signal processing portion may be configured to initiatea release period during which no chemical blocking agent control signalis generated after an interval determined relative to the onset ofgeneration of the chemical blocking agent control signal.

In some cases, the signal processing portion may be configured todetermine the onset of the second activity state in the subject andinitiate a release period during which no chemical blocking agentcontrol signal is generated responsive to detecting the second activitystate in the subject. The signal processing portion may be configured toinitiate the release period substantially immediately upon detection ofthe onset of the second activity state in the subject, or to initiatethe release period at a delay interval after detection of the onset ofthe second activity state in the subject.

Components of neural modulation systems of the type described herein maybe packaged in various manners. In some cases, all components of asystem may be packaged together. Such a package may be designed for useoutside the body, or designed for use inside the body in an implantablesystem. However, in many cases it may be desirable to package certaincomponents of the system separately. Communication between systemcomponents may be wireless, e.g. as described in U.S. Pat. No.6,208,894, which is incorporated herein by reference in its entirety.The system may include the capability for remote programming,interrogation, or telemetry, for example as described in U.S. Pat. No.7,263,405, which is incorporated herein by reference in its entirety.

FIG. 24 depicts an example of a neural modulation system 100 in which asensor (motion sensor 1102) and chemical blocking agent source arepackaged with signal processing portion 110 in package 1108. Motionsensor 1102 provides an input to signal processing portion 110 viasignal input structure 192. Signal processing portion 110 generateschemical blocking agent control signal 1112 which drives delivery ofchemical blocking agent 1114 by chemical blocking agent source 160.Package 1108 may be adapted to be positioned external to the body ofsubject 1055, and chemical blocking agent 1114 may pass through bodytissues to reach peripheral neural structure 1062. Chemical blockingagent source 160 may include, for example, components of aniontophoresis, electroporation, phonophoresis, sonophoresis, or othersystem configured to deliver a chemical blocking agent to the body ofthe subject sufficient to produce blocking of a nerve, as describedelsewhere herein. Package 1108 may be configured to secured to a limb(e.g., with a strap or elastic band) over a peripheral neural structure1062, so that the chemical blocking agent may be delivered to theperipheral neural structure. Generation of chemical blocking agentcontrol signal 1112 by signal processing portion 110 may be responsiveto a signal from motion sensor 1102, such that a chemical blocking agentmay be delivered to the peripheral neural structure when the limb is notin motion, for example. The peripheral neural structure may be, forexample, a sensory nerve, and blockage of neural activity therein may,for example, reduce or limit pain or inflammation, e.g. of arthritis,peripheral vascular disease, etc. In related embodiments, sensor 1102may be any of various types of sensors, as described elsewhere herein.

FIG. 25 depicts an example of a neural modulation system 100 in which animplanted sensor and implanted chemical blocking agent source are used.In this example, the implanted sensor may be sensing electrode 1152, andthe chemical blocking agent source 160 may be an infusion pump. Theinfusion pump may, for example, be as described in U.S. Pat. Nos.5,814,019 and 6,666,845, which are incorporated herein by reference intheir entirety. In other implanted devices, other chemical agentdelivery devices/mechanisms may be used, as described elsewhere herein.Sensing electrode 1152 and infusion pump (chemical blocking agent source160) may be implanted within the body of subject 1055, such that sensingelectrode 1152 may sense neural or muscular activity representative ofactivity of at least a portion of the body of the subject, and theinfusion pump (160) may deliver chemical blocking agent 1156 to aperipheral neural structure, peripheral nerve 1062. As used herein,“implanted” means located or positioned, either temporarily orpermanently, within the body of the subject. Signal processing portion110 may be packaged separately, e.g. in package 1160. Sensing electrode1152 may provide an input to signal processing portion 110 via signalinput structure 192. Signal processing portion 110 may generate chemicalblocking agent control signal 1164 for driving delivery of chemicalblocking agent 1156 by infusion pump 1154. Package 1160 may be implantedwithin the body of subject 1055, or located external to body of subject1055. In either case, signals may be transmitted between signalprocessing portion 110 and sensing electrode 1152 and chemical blockingagent source 160 (infusion pump) via a wire or cable, optical ink,acoustic link, radio frequency or other electromagnetic link, or otherwireless communication link, as is known to those of skill in the art.

Blockage of neural activity may reduce or limit pain or inflammation. Inan application, as depicted in FIG. 25, for example, sensing electrode1152 and chemical blocking agent source 160 (the infusion pump) may beimplanted adjacent a sensory nerve innervating a limb, appendage, orjoint (for example, a knee) that has suffered injury and/or damage, withthe goal of limiting the progression of arthritis that would otherwisebe associated with the injury or damage.

FIG. 26 depicts in further detail an example of a neural modulationsystem 100 in which components are packaged so that some can be usedlocally (e.g. implanted in the body or positioned on or near the bodysurface) while others are used remotely, which in this context may be ina separate package located relatively close by (i.e. in, on or near thebody), or at a distant location such as across a room, in a separateroom, or in a separate building). Neural modulation system 100 includeslocal portion 1202 and remote portion 1204. Local portion 1202 may beimplanted in the body of a subject or positioned on or near the bodysurface, while remote portion 1204 may be located remotely from localportion 1202. Local portion 1202 may include sensor 1206 and chemicalblocking agent source 160. Local portion 1202 may also include localcircuitry portion 1210 and local receiver/transmitter 1212. Acorresponding remote receiver/transmitter 1214 in remote portion 1204permits the transmission of data and instructions between local portion1202 and remote portion 1204. In some embodiments, power may also betransmitted between remote portion 1204 and local portion 1202.Alternatively, or in addition, one or both of local portion 1202 andremote portion 1204 may include a power source (e.g., a battery or otherpower source as known to those of skill in the art). Remote portion 1204may include remote circuitry 1216, which may include signal processingportion 1218. The signal processing portion of the system may includeonly signal processing portion 1218 in remote portion 1204, or it mayinclude both signal processing portion 1218 in remote portion 1204 andsignal processing circuitry 1220 in local portion 1202. Alternatively,in some embodiments, the signal processing portion may include signalprocessing portion 1220 in local portion 1202 and remote circuitry 1216may be devoted to other functions.

Components packaged separately may be operatively connected to othercomponents by cables, a wireless link (which may be optical,electromagnetic, acoustic, etc.). Separately packaged components may besuited for use outside or inside the body. In some embodiments, somecomponents may be positioned inside the body while other are positionedoutside the body during use. In some embodiments, the signal processingportion may be configured to perform encryption of signals transmittedto separately packaged and/or remote components or device portion, e.g.a chemical blocking agent control signal. Similarly, the signalprocessing portion may be configured to perform decryption of signalsreceived from, e.g., a user input device, via a signal input structureor override signal input structure. Encryption/decryption may beperformed by standard methods as known to those of skill in the art, forexample, as used in computers, networks, mobile telephones, wirelessmicrophones, wireless intercom systems, Bluetooth devices, and so forth.Encryption/decryption may be used in order to provide securetransmission of information, for example for protecting privacy ofpersonal information and/or for avoiding interference between multipledevices used in the same area.

In some embodiments, a user input device may be used in place of (or inaddition to) a sensor in order to provide indication of an activity oruse state of all or a portion of the body of the subject. Such a systemis depicted in schematic form in FIG. 27. As shown in FIG. 27, neuralmodulation system 100 may include a signal input structure 192configured to receive a signal 1254 indicative of an activity state ofat least a portion of a body of a subject 1256 innervated by aperipheral neural structure 1258; a user input device (switch 1260)operatively connected to the signal input structure 192 and configuredto generate a signal 1254 responsive to a user input indicative of anactivity state of at least a portion of the body of a subject 1256innervated by the peripheral neural structure 1258. For example, switch1260 may be set to the “on” setting when the subject is entering a firstactivity state, and set to the “off” setting when the subject isentering a second activity state. Neural modulation system 100 alsoincludes signal processing portion 110 configured to distinguish a firstactivity state of the at least a portion of the body of the subject 1256innervated by the peripheral neural structure 1258 from a secondactivity state of the at least a portion of the body of the subject 1256innervated by the peripheral neural structure 1258 from the signal 1254received at the signal input structure 192 (e.g., by detecting the “on”or “off” setting of switch 1260); and generate a chemical blocking agentcontrol signal 1264 for driving delivery of a chemical blocking agent1266 configured to reversibly block conduction in the peripheral neuralstructure 1258 of the body of subject 1256 during at least a portion ofthe first activity state. Chemical blocking agent 1266 is delivered by achemical blocking agent source 160 responsive to chemical blocking agentcontrol signal 1264.

A user of the neural modulation system depicted in FIG. 27 (the subjector another party, such as a medical care-giver or assistant) may useuser input device (e.g., switch 1260) to indicate that the subject iscurrently resting or inactive (e.g., sitting in a chair or lying in bed)or about to begin a period of rest or inactivity, e.g., by changing thesetting of switch, as described above. Similarly, a user of the systemmay also use the user input device to indicate the end of a period ofrest or inactivity. The user input device may include various types ofuser input devices, as are known to those of skill in the art. Forexample, the user input device may include one or more of the following:a voice-activated or other sound-activated input device, e.g. amicrophone, a user-activated switch or knob, a keyboard, a mouse orother pointing device, a touch-screen or other user activated inputdevices.

The foregoing are examples, and various other devices that allow thesubject or other user to signal a change (or expected change) inactivity state may be used in practice.

As discussed in connection with systems in which sensors are used toprovide indication of an activity or use state of all or a portion ofthe body of the subject, the various components of the system may bepackaged together or separately, located locally or remotely, inside oroutside the body of the subject, as depicted in FIGS. 23-28. Forexample, FIG. 27 shows an example of a neural modulation system in whichswitch 1260 is packaged separately from the signal processing portion110 and is located outside of the body of subject 1256, while chemicalblocking agent source 160 is packaged with signal processing portion110. Signal processing portion 110 and chemical blocking agent source160 may be in a package configured to be placed against the subject'sbody as the subject rests, while switch 1260 may be connected to signalprocessing portion 110 with a cable, for example (or, alternatively, awireless connections such as an optical or RF connection). The subjectmay toggle switch 1260 to indicate the beginning or end of a rest periodduring which the chemical blocking agent is to be delivered. Chemicalblocking agent source 160 may be configured to generate a chemicalblocking agent sufficient to block conduction in peripheral neuralstructure. Peripheral neural structure 1258 may be blocked with the goalof producing a particular beneficial effect, such as to limit theprogression of an inflammatory process (e.g. in diabetes, arthritis,vascular disease).

FIG. 28 depicts a further example of a neural modulation system 100 inwhich user input device 1302 is packaged separately from signalprocessing portion 110, providing signal 1306 to signal input structure192. Signal processing portion 110 generates chemical blocking agentcontrol signal 1310, which is provided (e.g., transmitted) to chemicalblocking agent source 160, which is implanted within the body of subject1256. As discussed previously, schemical blocking agent source 160delivers chemical blocking agent 1314 for blocking conduction inperipheral neural structure 1258 in body of subject 1256. Otherarrangements of system components are possible, and systems as describedgenerally herein are not limited to the specific arrangements ofcomponents depicted in the figures.

A schematic diagram showing components and operation of a signalprocessing portion 110 of a neural modulation system 100 is shown inFIG. 29. The functional relationship of signal processing portion 110 toother components of neural modulation system 100 is also shown. As notedpreviously, signal processing portion 110 and other system componentsmay be powered by a single power source, as shown in FIG. 28 as powersource 1354; or multiple power sources. Signal processing portion 110may receive as input signals from one or more sensors 1356 and/or one ormore user input devices 1358 via signal input structure 192, andoptionally, a signal from override signal input structure 1360. Signalprocessing portion 110 may generate as output chemical blocking agentcontrol signal 1361 for driving chemical blocking agent source 160 todeliver a chemical blocking agent.

Signal processing portion 110 may include electrical circuitry 1364 forperforming signal processing functions including but not limited toamplification, filtering, signal averaging, thresholding,variable-changing, waveform analysis, variable (e.g., time- orspatial-frequency) domain transformation, convolution, cross-spectralanalysis, feature or pattern recognition or extraction, processingperformed relative to data-stored-in-memory, etc., or a combination orconcatenation of any or all of these, as is known to those of skill inthe art of signal processing, whether such operations may be done insoftware, firmware or hardware or combinations of these. Electricalcircuitry 1364 may also be configured to generate chemical blockingagent control signal 1361 for driving chemical blocking agent source160. In some embodiments, chemical blocking agent control signal 1361may include a primary chemical blocking agent control signal for drivingprimary chemical blocking agent source 160, and electrical circuitry1364 may also be configured to generate secondary chemical blockingagent control signal 1386 for driving secondary chemical blocking agentsource 1388. Detection of the onset or end of an activity state is notlimited to threshold-based determinations, but may include various othertypes of signal processing as known to those of skill in the art; forexample analysis of the trend of the signal may be used to predict theonset of an activity state. Accordingly, operations performed inresponse to detection or determination of the onset of a particularactivity state may in some cases be based upon the predicted onset of anactivity state, and may occur before, after, or simultaneously with thepredicted onset of an activity state. Electrical circuitry or othercomponents of a signal processing portion may accordingly be configuredto cause delivery of a chemical blocking agent or to initiate a releaseperiod prior to, simultaneously with, or subsequently to the predictedthe onset of an activity state in the subject.

The chemical blocking agent may be delivered with a repetitive orcyclical delivery pattern according to a detected signal indicative ofat least one activity state in the subject and/or according to a pre-setschedule. Signal processing portion 110 may include at least one signalbearing medium 1366 that may contain chemical blocking agent pattern1368, which specifies the pattern of delivery of a chemical blockingagent, as a function of time, and, in some cases, spatial location.Signal bearing medium 1366 may also include chemical blocking agentparameters 1370 related to generating chemical blocking agent controlsignal 1361 according to a detected signal from sensor 1356 or userinput 1358. Stimulus parameters 1370 may include constants and/orvariables to be used in calculations of chemical blocking agent controlsignal 1360 as a function of the detected signal. Signal bearing medium1366 may include instructions 1372, which may relate to one or more ofreceiving or acquiring signals on signal input structure 192, processingthe signals, generating chemical blocking agent control signal 1361,storing data (e.g. signals or parameters representing some or all ofsensor or user input, chemical blocking agent control signal, etc.) indata storage location 1374, and instructions related to transmittingand/or receiving data or instructions via transmitter/receiver circuitry1376. Electrical circuitry 1364 and signal bearing medium 1366 mayoptionally include instructions, patterns, and/or parameters for use ingenerating release stimulus control signal 1380 for producingdiscontinuation of delivery of a chemical blocking agent by chemicalblocking agent source 160, and instruction, patterns, and/or parametersfor use in generating reversing stimulus control signal 1382 for drivinggeneration of a reversing stimulus by reversing stimulus source 1384.

In a general sense, those skilled in the art will recognize that thevarious aspects described herein that can be implemented, individuallyand/or collectively, by a wide range of hardware, software, firmware, orany combination thereof can be viewed as being composed of various typesof “electrical circuitry.” Consequently, as used herein “electricalcircuitry” includes, but is not limited to, electrical circuitry havingat least one discrete electrical circuit, electrical circuitry having atleast one integrated circuit, electrical circuitry having at least oneapplication specific integrated circuit, electrical circuitry forming ageneral purpose computing device configured by a computer program (e.g.,a general purpose computer configured by a computer program that atleast partially carries out processes and/or devices described herein,or a microprocessor configured by a computer program that at leastpartially carries out processes and/or devices described herein),electrical circuitry forming a memory device (e.g., forms of randomaccess memory), and/or electrical circuitry forming a communicationsdevice (e.g., a modem, communications switch, or optical-electricalequipment). Those having skill in the art will recognize that thesubject matter described herein may be implemented in an analog ordigital fashion or some combination thereof.

Operation of neural modulation devices as described herein may beperformed under the control of hardware (e.g. analog or digitalelectronic circuitry). Circuitry for switching, signal generation,sensing, timing control etc. is well known and may be constructed bythose of skill in the art of electronics. In some embodiments, controlof neural modulation devices as described herein may be performed undermicroprocessor control. Instructions to be executed by a microprocessormay be stored in hardware, firmware, or software (e.g. as an ASIC,instructions burned into an EEPROM, instructions stored in various typesof memory devices/structures) on various types of signal-bearing media.Instructions for controlling neural modulation devices as describedherein may be used, for example to implement methods as outlined, e.g.in FIGS. 5, 7, 8, and 14, 16, 18, 19, and 21. Instructions carried on asignal bearing medium may form a permanent or temporary component of asystem including additional device components. Signal bearing mediaused, e.g. as depicted in FIG. 29, may include both instructions forcontrolling neural modulation device, and also stored data orparameters. Data, parameters, and instructions may be stored on morethan one types of media during the practice of the invention (e.g.,partially in device memory, partially on a removable medium, etc.).

Methods as described herein may include storing or saving informationregarding device operation on the device, or transmitting suchinformation to a remote location for storage or evaluation. Informationmay include, but is not limited to including device settings, parametersand other information relating to production of blocking and reversingstimuli, and sensed activity level or activity state of a subject,regarding producing a reversible conduction block.

A signal processing portion used in various embodiments as disclosedherein may be configured to perform the various described steps byappropriately configured analog or digital hardware, by instructionsencoded in software or firmware, or combinations thereof, or by othermethods as are known to those of skill in the art. Those having skill inthe art will recognize that the state of the art has progressed to thepoint where there is little distinction left between hardware andsoftware implementations of aspects of systems; the use of hardware orsoftware is generally (but not always, in that in certain contexts thechoice between hardware and software can become significant) a designchoice representing cost vs. efficiency tradeoffs. Those having skill inthe art will appreciate that there are various vehicles by whichprocesses and/or systems and/or other technologies described herein canbe effected (e.g., hardware, software, and/or firmware), and that thepreferred vehicle will vary with the context in which the processesand/or systems and/or other technologies are deployed. For example, ifan implementer determines that speed and accuracy are paramount, theimplementer may opt for a mainly hardware and/or firmware vehicle;alternatively, if flexibility is paramount, the implementer may opt fora mainly software implementation; or, yet again alternatively, theimplementer may opt for some combination of hardware, software, and/orfirmware. Hence, there are several possible vehicles by which theprocesses and/or devices and/or other technologies described herein maybe effected, none of which is inherently superior to the other in thatany vehicle to be utilized is a choice dependent upon the context inwhich the vehicle will be deployed and the specific concerns (e.g.,speed, flexibility, or predictability) of the implementer, any of whichmay vary.

The foregoing detailed description has set forth various embodiments ofthe devices and/or processes via the use of block diagrams, flowcharts,and/or examples. Insofar as such block diagrams, flowcharts, and/orexamples contain one or more functions and/or operations, it will beunderstood by those within the art that each function and/or operationwithin such block diagrams, flowcharts, or examples can be implemented,individually and/or collectively, by a wide range of hardware, software,firmware, or virtually any combination thereof. In one embodiment,several portions of the subject matter described herein may beimplemented via Application Specific Integrated Circuits (ASICs), FieldProgrammable Gate Arrays (FPGAs), digital signal processors (DSPs), orother integrated formats. However, those skilled in the art willrecognize that some aspects of the embodiments disclosed herein, inwhole or in part, can be equivalently implemented in integratedcircuits, as one or more computer programs running on one or morecomputers (e.g., as one or more programs running on one or more computersystems), as one or more programs running on one or more processors(e.g., as one or more programs running on one or more microprocessors),as firmware, or as virtually any combination thereof, and that designingthe circuitry and/or writing the code for the software and or firmwarewould be well within the skill of one of skill in the art in light ofthis disclosure. In addition, those skilled in the art will appreciatethat the mechanisms of the subject matter described herein are capableof being distributed as a program product in a variety of forms, andthat an illustrative embodiment of the subject matter described hereinapplies regardless of the particular type of signal bearing medium usedto actually carry out the distribution. Examples of a signal bearingmedium include, but are not limited to, the following: a recordable typemedium such as a floppy disk, a hard disk drive, a Compact Disc (CD), aDigital Video Disk (DVD), a digital tape, a computer memory, etc.; and atransmission type medium such as a digital and/or an analogcommunication medium (e.g., a fiber optic cable, a waveguide, a wiredcommunications link, a wireless communication link, etc.).

One skilled in the art will recognize that the herein describedcomponents (e.g., steps), devices, and objects and the discussionaccompanying them are used as examples for the sake of conceptualclarity and that various configuration modifications are within theskill of those in the art. Consequently, as used herein, the specificexemplars set forth and the accompanying discussion are intended to berepresentative of their more general classes. In general, use of anyspecific exemplar herein is also intended to be representative of itsclass, and the non-inclusion of such specific components (e.g., steps),devices, and objects herein should not be taken as indicating thatlimitation is desired.

The contents of the publications, journal articles, books, patents, andpublished patent applications referenced herein are incorporated hereinby reference to the extent that they do not conflict with the instantdisclosure.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations are not expressly set forth herein for sakeof clarity.

The herein described subject matter sometimes illustrates differentcomponents contained within, or connected with, different othercomponents. It is to be understood that such depicted architectures aremerely exemplary, and that in fact many other architectures can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” such that the desired functionality isachieved. Hence, any two components herein combined to achieve aparticular functionality can be seen as “associated with” each othersuch that the desired functionality is achieved, irrespective ofarchitectures or intermedial components. Likewise, any two components soassociated can also be viewed as being “operably connected”, or“operably coupled”, to each other to achieve the desired functionality,and any two components capable of being so associated can also be viewedas being “operably couplable”, to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to physically mateable and/or physically interactingcomponents and/or wirelessly interactable and/or wirelessly interactingcomponents and/or logically interacting and/or logically interactablecomponents.

In some instances, one or more components may be referred to herein as“configured to.” Those skilled in the art will recognize that“configured to” can generally encompass active-state components and/orinactive-state components and/or standby-state components, etc. unlesscontext requires otherwise.

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent to those skilled inthe art that, based upon the teachings herein, changes and modificationsmay be made without departing from the subject matter described hereinand its broader aspects and, therefore, the appended claims are toencompass within their scope all such changes and modifications as arewithin the true spirit and scope of the subject matter described herein.Furthermore, it is to be understood that the invention is defined by theappended claims. It will be understood by those within the art that, ingeneral, terms used herein, and especially in the appended claims (e.g.,bodies of the appended claims) are generally intended as “open” terms(e.g., the term “including” should be interpreted as “including but notlimited to,” the term “having” should be interpreted as “having atleast,” the term “includes” should be interpreted as “includes but isnot limited to,” etc.). It will be further understood by those withinthe art that if a specific number of an introduced claim recitation isintended, such an intent will be explicitly recited in the claim, and inthe absence of such recitation no such intent is present. For example,as an aid to understanding, the following appended claims may containusage of the introductory phrases “at least one” and “one or more” tointroduce claim recitations. However, the use of such phrases should notbe construed to imply that the introduction of a claim recitation by theindefinite articles “a” or “an” limits any particular claim containingsuch introduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” and/or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould typically be interpreted to mean at least the recited number(e.g., the bare recitation of “two recitations,” without othermodifiers, typically means at least two recitations, or two or morerecitations). Furthermore, in those instances where a conventionanalogous to “at least one of A, B, and C, etc.” is used, in generalsuch a construction is intended in the sense one having skill in the artwould understand the convention (e.g., “a system having at least one ofA, B, and C” would include but not be limited to systems that have Aalone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). In those instances where aconvention analogous to “at least one of A, B, or C, etc.” is used, ingeneral such a construction is intended in the sense one having skill inthe art would understand the convention (e.g., “a system having at leastone of A, B, or C” would include but not be limited to systems that haveA alone, B alone, C alone, A and B together, A and C together, B and Ctogether, and/or A, B, and C together, etc.). It will be furtherunderstood by those within the art that virtually any disjunctive wordand/or phrase presenting two or more alternative terms, whether in thedescription, claims, or drawings, should be understood to contemplatethe possibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

With respect to the appended claims, those skilled in the art willappreciate that recited operations therein may generally be performed inany order. Examples of such alternate orderings may include overlapping,interleaved, interrupted, reordered, incremental, preparatory,supplemental, simultaneous, reverse, or other variant orderings, unlesscontext dictates otherwise. With respect to context, even terms like“responsive to,” “related to,” or other past-tense adjectives aregenerally not intended to exclude such variants, unless context dictatesotherwise.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is:
 1. A method of modulating an immune or inflammatoryresponse or process in a subject in need thereof, comprising: deliveringan ultrasonic blocking stimulus sufficient to produce a reversibleconduction block in at least a portion of a sensory nerve of a subjectwith an ultrasound source; and repeating delivery of the ultrasonicblocking stimulus in a cyclical application pattern for a duration orperiod sufficient to modulate the immune or inflammatory response orprocess.
 2. The method of claim 1, comprising delivering the ultrasonicblocking stimulus with an ultrasound source secured to a limb of thesubject.
 3. The method of claim 1, wherein the delivery of theultrasonic blocking stimulus in a cyclical application pattern isrepeated until a measurement of an indicator of immune or inflammatoryresponse or process indicates that the modulation of the immune orinflammatory response or process has been obtained.
 4. The method ofclaim 1, comprising: measuring an indicator of an immune or inflammatoryresponse or process in a region of the body of the subject innervated bythe sensory nerve; and determining whether a modulation of the immune orinflammatory response or process has been obtained based on themeasurement of the indicator of the immune or inflammatory response orprocess.
 5. The method of claim 4, wherein the delivery of theultrasonic blocking stimulus in a cyclical application pattern isrepeated until measurement of the indicator of immune or inflammatoryresponse or process indicates that the modulation of the immune orinflammatory response or process has been obtained.
 6. The method ofclaim 1, wherein a cycle of the cyclical application pattern includes: ablocking period during which the ultrasonic blocking stimulus is appliedat least intermittently, the blocking period coinciding at least in partwith a first activity state in the subject; and a release period duringwhich no ultrasonic blocking stimulus is applied, the release periodcoinciding at least in part with a second activity state in the subject.7. The method of claim 6, comprising: detecting at least one of theonset of the first activity state and the onset of the second activitystate in the subject.
 8. The method of claim 6, comprising receiving thesignal indicative of at least one of the first activity state and thesecond activity state of the subject from a user input device.
 9. Themethod of claim 6, comprising receiving the signal indicative of atleast one of the first activity state and the second activity state ofthe subject from a sensor associated with the package adapted to sense aparameter indicative of an activity state of the subject.
 10. The methodof claim 1, wherein the sensory nerve innervates at least a portion of ajoint of the subject.
 11. The method of claim 1, wherein the sensorynerve innervates at least a portion of a limb of the subject.
 12. Themethod of claim 1, wherein the sensory nerve innervates at least aportion of a digit of the subject.
 13. The method of claim 1, whereinthe immune or inflammatory response or process is associated with anarthritic condition in the subject.
 14. The method of claim 1, whereinthe immune or inflammatory response or process is associated with aneuropathy in the subject.
 15. The method of claim 1, wherein the immuneor inflammatory response or process is associated with a vasculardisease in the subject.
 16. A neural modulation system, comprising: apackage configured to be secured to a limb of a subject adjacent a skinsurface in the vicinity of a sensory nerve; a signal input structureconfigured to receive a signal indicative of the activity state of thesubject; an ultrasound source within the package, the ultrasound sourceconfigured to produce an ultrasonic blocking signal sufficient toreversibly block conduction in the sensory nerve; and a signalprocessing portion within the package, the signal processing portionincluding circuitry configured to: distinguish a first activity state ofthe subject from a second activity state of the subject based on thesignal received at the signal input structure; and generate a blockingstimulus control signal for driving production of the ultrasonicblocking stimulus by the ultrasound source in a cyclical applicationpattern in response to at least one of the first activity state and thesecond activity state.
 17. The neural modulation system of claim 16,wherein the cyclical application pattern includes: a blocking periodduring which the ultrasonic blocking stimulus is applied at leastintermittently, the blocking period coinciding at least in part with thefirst activity state in the subject; and a release period during whichno ultrasonic blocking stimulus is applied, the release periodcoinciding at least in part with the second activity state in thesubject.
 18. The neural modulation system of claim 17, wherein thesignal input structure is configured to receive the signal indicative ofthe activity state of the subject from the sensor.
 19. The neuralmodulation system of claim 18, wherein the sensor includes at least oneof a pressure sensor, a force sensor, a chemical sensor, a temperaturesensor, an electrical sensor, a magnetic sensor, an optical sensor, amotion sensor, an accelerometer, a gyro, a mercury switch, apiezoelectric device and a switch.
 20. The neural modulation system ofclaim 18, wherein the sensor includes a physiological sensor configuredto generate a signal indicative of activity of at least one of a heart,a peripheral neural system, a muscle, or a body temperature of thesubject.
 21. The neural modulation system of claim 16, comprising: asensor associated with the package adapted to sense a parameterindicative of an activity state of the subject.
 22. The neuralmodulation system of claim 16, wherein the signal input structure isconfigured to receive the signal indicative of the activity state of thesubject from a user input device.
 23. The neural modulation system ofclaim 22, wherein the user input device includes at least one of a voiceor sound activated input, a switch, a knob, a keyboard, a mouse, a touchscreen, a remote controller, a cell phone, or a remote computer operatedby the user.
 24. The neural modulation system of claim 16, comprising:at least one of a wrap adapted to be positioned around at least aportion of the body of the subject, a bandage or patch configured to beadhered or secured to at least a portion of skin of the subject, abracelet, an anklet, an armband, a cuff, a fitted garment, or an item ofclothing configured to be worn by the subject.
 25. The neural modulationsystem of claim 16, wherein the package is configured to be secured tothe limb of the subject with a strap or elastic band.
 26. An article ofmanufacture, comprising: one or more non-transitory machine-readabledata storage media bearing one or more instructions relating to:delivering an ultrasonic blocking stimulus sufficient to produce areversible conduction block in at least a portion of a sensory nerve ofa subject with an ultrasound source secured to a limb of a subject; andrepeating delivery of the ultrasonic blocking stimulus in a cyclicalapplication pattern for a duration or period sufficient to modulate theimmune or inflammatory response or process.
 27. The article ofmanufacture of claim 26, wherein the one or more non-transitorymachine-readable data storage media bear one or more instructionsrelating to: receiving a measurement indicative of an immune orinflammatory response or process in a region of the body of the subjectinnervated by the sensory nerve; and determining whether a modulation ofthe immune or inflammatory response or process has been obtained basedon the measurement indicative of the immune or inflammatory response orprocess.
 28. The article of manufacture of claim 26, wherein the one ormore non-transitory machine-readable data storage media bear one or moreinstructions relating to: repeating delivery of the ultrasonic blockingstimulus in a cyclical application pattern until the measurementindicative of the immune or inflammatory response or process indicatesthat the modulation of the immune or inflammatory response or processhas been obtained.
 29. The article of manufacture of claim 26, whereinthe one or more instructions relating to repeating delivery of theultrasonic blocking stimulus in a cyclical application pattern includeone or more instructions relating to repeating delivery of theultrasonic blocking stimulus in a cyclical application pattern having: ablocking period during which the ultrasonic blocking stimulus is appliedat least intermittently, the blocking period coinciding at least in partwith a first activity state in the subject; and a release period duringwhich no ultrasonic blocking stimulus is applied, the release periodcoinciding at least in part with a second activity state in the subject.30. The article of manufacture of claim 29, wherein the one or morenon-transitory machine-readable data storage media bear one or moreinstructions relating to: detecting at least one of the onset of thefirst activity state and the onset of the second activity state in thesubject.
 31. The article of manufacture of claim 29, wherein the one ormore non-transitory machine-readable data storage media bear one or moreinstructions relating to: receiving the signal indicative of at leastone of the first activity state and the second activity state of thesubject from a sensor associated with the package.